- Open Access
Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications
© López-Novoa et al; licensee BioMed Central Ltd. 2011
Received: 6 August 2010
Accepted: 20 January 2011
Published: 20 January 2011
Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed.
Introduction to chronic kidney disease
Definition and clinical course
Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised, mainly resulting from damage to renal structures. Most, but not all, forms of CKD are irreversible and progressive. Renal damage includes (i) nephron loss due to glomerular or tubule cell deletion, (ii) fibrosis affecting both the glomeruli and the tubules, and (iii) renal vasculature alterations. CKD results from a variety of causes such as diabetes, hypertension, nephritis, inflammatory and infiltrative diseases, renal and systemic infections (e.g. streptococcal infections, bacterial endocarditis, human immunodeficiency virus -HIV-, hepatitis B and C, etc.), polycystic kidney disease, autoimmune diseases (e.g. systemic lupus erythematosus), renal hypoxia, trauma, nephrolithiasis and obstruction of the lower urinary ways, chemical toxicity and others. In a variable number of cases, renal injury by any of these causes evolves towards a chronic, progressive and irreversible stage of increasing damage and renal dysfunction wherein, eventually, renal replacement therapy (RRT, namely dialysis or renal transplant) becomes necessary [1, 2].
Stages of chronic renal disease defined by the National Kidney Foundation of the U.S.A. according to the glomerular filtration rate (GFR, in mL/min per 1.73 m2 of body surface), and common manifestations observed in each stage.
↑ Parathyroid hormone, ↓renal calcium reabsorption
Left ventricular hypertrophy, anemia secondary to erythropoietin deficiency
↑ Serum triglycerides, hyperphosphatemia, hyperkalemia, metabolic acidosis, fatigue, nausea, anorexia, bone pain
Renal failure: severe uremic symptoms
The term uremia or uremic syndrome refers to the clinical manifestations of CKD, which are derived from the inability of the kidneys to properly clear the blood of waste products. As a consequence, toxic substances usually eliminated through the urine become concentrated in the blood and cause progressive dysfunction of many (virtually all) other tissues and organs, seriously compromising well-being, quality of life and survival. For example, elevated serum uric acid is a marker for decreased renal function, may have a mechanistic role in the incidence and progression of renal functional decline [7, 8]. In a recent study performed on 900 healthy normotensive, adult blood donors higher serum uric acid levels were highly significantly associated with a greater likelihood of reduced glomerular filtration . Further clinical trials are needed to determine if uric acid lowering therapy will be effective in preventing CKD. However, kidney damage must occur to a significant extent before function becomes altered. Uremic signs and symptoms start to be vaguely detectable when at least two thirds of the total number of nephrons is functionally lost. Until then, CKD runs apparently silent. This is due to the ability of the remaining nephrons to undergo hypertrophy and functionally compensate for those that are lost .
A representation of GFR evolution in time is a helpful estimation of renal disease progression rate. It is useful to monitor CKD as well as to predict the time for RRT. Progression rate is highly dependent on the underlying cause but, due to genetic heterogeneity, it is also very variable among subjects with the same etiology . In general, tubulointerstitial diseases progress more slowly than glomerular ones, and also than diabetic kidney disease, hypertension-associated disease and polycystic kidney disease. A complete diagnosis includes detection, determination of stage of disease, assessment of etiology, presence of comorbid conditions and estimation of progression rate [3–6].
The key and yet unmet issue in CKD is why, and through which mechanisms, persistence of triggering damage or repetitive bouts, initially repairable as in acute damage events, eventually go beyond a no return point, after which non reversible chronicity ensues. The responses to these questions are beyond our present knowledge of CKD pathology. The development of early diagnostic and prognosis markers, and effective, curative -not merely palliative or delaying- therapies critically depend on our finding answers to these largely ignored questions. Notwithstanding, knowledge has emerged in the last few decades on new mechanisms and molecular pathways that mediate the development of certain facets of chronic phenotypes. This knowledge is potentially useful for optimizing current therapies and for developing new ones. The purpose of this review is to describe the pathophysiological processes leading to tubular, interstitial, glomerular and renovascular chronic diseases, focused on the cellular and molecular mechanisms involved, making emphasis in those that are common for most CKDs regardless of aetiology.
A variety of renal injuries may eventually evolve to CKD . Disease may start in the tubules and interstitium (tubulointerstitial diseases), in the glomeruli (glomerular diseases) or even in the renal vascular tree (renovascular diseases), as a consequence of (i) systemic diseases such as diabetes and hypertension, (ii) autoimmune reactions and renal transplant rejection, (iii) the action of drugs, toxins and metals, (iv) infections, (v) mechanical damage, (vi) ischemia, (vii) obstruction of the urinary tract, (viii) primary genetic alterations, and (ix) undetermined causes (idiopathic). Yet, a number of conditions, like genetic cystic diseases, affect renal structures and function through mostly unspecific mechanisms, and evolve into CKD for undetermined reasons.
Some decades ago, the leading cause of CKD was glomerulonephritis secondary to infections. Antibiotics and improved sanitary conditions have laid the way to diabetes and hypertension as the first and second leading causes of end stage renal disease (ESRD) in the developed world, respectively . In fact, about 50% of ESRD patients (in the USA) are diabetic . According to this source, about 50-60% of all patients with CKD are hypertensive, and this figure increases to 90% in patients over 65 years. In the corresponding general population the incidence of hypertension is 11-13% and 50%, respectively. Alltogether, 70% of ESRD cases are due to diabetes and hypertension . Recently, several large-scale epidemiological studies [14–16] have identified obesity as an independent risk factor for CKD. The link between obesity and CKD is not fully explained by the association between obesity and diabetes or hypertension respectively . Hall et al.  described a progressive increase in the incidence of ESRD since the eighties, coinciding with an increase in obesity and decreased hypertension. Similarly, Chen et al.  showed an association between the metabolic syndrome and the risk of developing chronic renal failure. Both studies support the association between increased weight and kidney disease, although no direct causality link between obesity and CKD can yet be established .
A genetic predisposition for renal failure is demonstrated by the 3-9 times higher probability of ESRD in patients with a family history of CKD, compared to the general population . However, it is difficult to assess whether this predisposition is due to a specific susceptibility to undergo renal damage, or to other comorbid conditions generally accepted to have poly- or oligo-genetic components, like hypertension, diabetes or atherosclerosis. Still, this observation has launched the search for nephropathy susceptibility genes.
Except for monogenic diseases (e.g. polycystic renal disease) , genetic studies based on quantitative trait loci (QTLs) analysis and sub-pair analysis have been unable to demonstrate polymorphism associations valid for most forms of CKD. A number of polygenic minor gene-gene interactions have been associated with specific human CKD of different etiology, such as type 2 diabetic nephropathy . Several loci have been identified on chromosome 3q, 10q and 18q for diabetic nephropathies, and on 10q also for non-diabetic nephropathies . Recently MYH9 gene polymorphisms have been shown to account for much of the excess risk of HIV-associated nephropathy, hypertensive, diabetic and nondiabetic kidney disease in African Americans [25–27]. A number of mutations have been associated to focal and segmental glomerulosclerosis during the last decade including: (i) two polimorphisms of apolipoprotein L 1 (APOL1) have been associated to the disease in African descendents ; and (ii) genetic alterations in five proteins expressed in podocytes, namely podocin (NPHS2 gene) [29, 30], inverted formin (INF2 gene) , the transient receptor potential cation channel, subfamily C, member 6 (TRPC6 gene) , CD2 associated protein (CD2AP gene) , and alpha-actinin 4 (ACTN4 gene) .
Genetic analysis of renal damage-prone rats crossed with more resistant strains have revealed the existence of 15 loci associated with renal disease , three of which coincide with those found in human monogenic segmental glomerulosclerosis, Pima Indians kidney disease, and creatinine clearance impairment in African- and Caucasian-Americans [34, 35]. These studies highlight the potential predictive value of animal models for the identification of CKD-associated genes. Still, other genetic determinants present in humans and absent in most animal models, derived from the inter-race, inter-population and inter-individual genomic heterogeneity, may pose limitations to findings make in animals. For example, human leukocyte antigen (HLA)-dependency of renal disease prevalence has been demonstrated in several studies with human populations surveyed for e.g. diabetic nephropathy [36, 37] or membranous glomerulonephritis .
The terms tubular diseases, tubulointerstitial diseases, tubulointerstitial nephritis and tubulointerstitial nephropathies refer to a heterogeneous panel of alterations which primarily affect both cortical and medullary tubules and the interstitium, and secondarily other renal structures such as the glomeruli . Tubules are the main component of the renal parenchyma and receive the most part of injury in renal disease . Nevertheless, renal interstitium also plays an important role in tubulointerstitial nephropathies, since pathogenesis perpetuates in this compartment and interstitial alterations contribute to diminish renal function . The interstitium is formed by the intercellular scaffolding posed by the extracellular matrix (ECM) and basement membranes, in which several cell types can be found. Apart from those forming blood and lymphatic vessels, including microvascular pericytes, resident and infiltrated immune system cells can also be found (i.e. white blood cells including macrophages). Finally, fibroblasts and, especially under pathological conditions, myofibroblasts form part of the tubular interstitium. Primary tubulointerstitial diseases  are idiopathic, genetic or due to (i) the chemical action of toxics and drugs that accumulate in the tubules inducing apoptosis or necrosis of tubular epithelial cells; (ii) infection and inflammation of the tubulointerstitium as a result of reflux/chronic pyelonephritis or other causes; (iii) increased intratubular pressure induced by mechanical stress and related to obstruction of lower urinary tract caused by lithiasis, prostatitis, fibrosis, or retroperitoneal tumors; and (iv) transplant rejection due to immune response. In many cases, the cause of the disease remains unknown. Renal function progressively deteriorates as a consequence of dysfunctional processes of tubular reabsorption and secretion, activation of tubular cells with recruitment of inflammatory mediators, progressive tubule loss and tissue scarring, and eventual damage of other renal structures (e.g. the glomeruli).
Independently of the triggering cause, characteristic hallmarks of tubulointerstitial diseases are tubular atrophy, interstitial fibrosis and cell infiltration , resulting in a significant increment in interstitial volume [42, 43]. In early stages, glomerular filtration becomes slowly altered, and tubular dysfunction constitutes the main manifestation of tubulointerstitial nephropathies [39, 44]. In contrast to glomerular diseases, in tubulointerstitial diseases hypertension appears late and only after a significant fall of GFR [45–47]. Proximal tubule alterations induce bicarbonaturia, β2-microglobulinuria, glucosuria and aminoaciduria. Distal alterations induce tubular acidosis, hyperkalemia and sodium loss . Structural alterations in medulla cause nephrogenic diabetes insipidus that is clinically manifested as polyuria and nocturia .
Initial damage and cell activation
As a consequence of the damage inflicted to tubular structures by the triggering insult, an initially restorative response starts, which eventually corrupts into a pathological vicious cycle of interstitial fibrosis and tissue destruction. Depending on the insult, tubular epithelial cell necrosis, apoptosis, or both are observed. In a restorative effort, an inflammatory response is implemented and tubular cells proliferate to substitute for dead cells. For unknown reasons, under undetermined circumstances the restorative process (in this and the next phases -see below-) loses the appropriate regulation and takes an irreversible self-destructive course that does not need the presence of the initial insult to progress. Interstitial fibrosis results from a deregulated process of fibrogenesis initially required to rebuild the normal tissue structure posed by ECM and basement membranes . Rather early, interstitial fibrosis gains a central pathological role, scars the interstitium and epithelial areas that should have been repaired with new epithelial tubular cells, and induces further tissue damage and destruction through apoptosis and phenotypical transdifferentiation of epithelial tubular cells.
Main molecular mediators known to participate in the pathophysiological process of tubular degeneration and interstitial fibrosis, grouped according to their most important effect.
FBR & EMT
1. Fibrosis and EMT
TC, F, MF, P, iG
TC, F, MF
TC, F, MF
Activates TGF-β 
Decorin and biglycan
TC, F, MF
F, MF, TC
TC, F, MF
ECM accumulation and fibrosis 
TC, F, MF
Complement C3 and C4
TC, P, iG
ICAM-1 and VCAM-1
TC, F, MF
3. Tubular damage
Tubular damage and fibrosis 
TNF-α, IFN-γ, Tweak
EC, TC, P
FBR & EMT
1. Fibrosis and EMT
F, MF, TC
Inhibits EMT 
MMP-2 and 9
Degrade collagen IV 
Inhibits EMT and fibrosis 
Infiltrated cells, spanning the endothelium of peritubular capillaries , or proliferating resident macrophages , essentially contribute to the progression of renal parenchymal damage in CKD . Chemoattractans secreted from the basolateral membrane of damaged tubular cells or crossing the tubule wall from the luminal filtrate, recruit inflammatory cells (monocytes and lymphocytes) and induce fibroblast proliferation. This event, in turn, potentiates a vicious circle of inflammation and fibrogenesis . Specifically, activated tubular cells synthesize the chemoattractant cytokine MCP-1 as a response to protein overload . Tubular MCP-1 production has been documented in patients with CKD  and animal models . MCP-1 may also proceed from the proteinuric glomerular ultrafiltrate, originating in plasma or damaged glomeruli. Importantly, MCP-1-deficient mice undergo a milder interstitial inflammation and show a higher life expectancy than controls during CKD . Interstitial accumulation of monocytes and activation of resident macrophages amplify the inflammatory response and lymphocyte diapedesis , and contribute to damage progression as sources of profibrotic factors .
Damage also activates renal fibroblasts, which proliferate and constitute an important source of pathological, fibrogenic ECM components, such as collagens and fibronectin [42, 61, 75, 76] in response to many factors released from primed tubular cells, white cells and fibroblasts themselves. These molecules include cytokines and growth factors, such as transforming growth factor beta1 (TGF-β1), MCP-1, connective tissue growth factor (CTGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), platelet activating factor (PAF), and interleukins (ILs) 1, 4 and 6, as well as vasoactive molecules (e.g. angiotensin II and endothelin-1), and ECM-cell interaction molecules (e.g. integrins, hialuronic acid) [; table 2; figure 3].
In most forms of CKD, the number of interstitial myofibroblasts is increased, and strongly correlates with the degree of interstitial fibrosis [77, 78]. Activated myofibroblasts constitute a predicting histological marker for the progression of renal disease [79, 80]. Myofibroblasts are the main source of excessive ECM in fibrotic nephropathies . Myofibroblasts may be originated by trans-differentiation of fibroblasts, tubular epithelial cells, vascular pericytes and macrophages [57, 81, 82]. In diseased kidneys, myofibroblasts accumulate around damaged tubules and arterioles. Fibrosis-induced microvascular obliteration and vasoconstriction is mediated by vasoactive factors (e.g. angiotensin II and endothelin-1), which produce ischemia, glomerular hemodynamic alterations and further angiotensin II production, all of which amplify fibrogenesis and perpetuate damage [83, 84] with the concourse of TGF-β1 and PDGF [85, 86].
Under pathological conditions during CKDs, damaged renal tissue is replaced by a scar-like formation, characterized by excessive ECM accumulation and progressive renal fibrosis. Fibrosis is the consequence of (i) an increased synthesis and release of matrix proteins from tubular cells, fibroblasts and mostly myofibroblasts, and (ii) a decreased degradation of ECM components [87, 88]. During progression of tubulointerstitial fibrosis, fibroblasts show a higher proliferation rate, differentiation to myofibroblasts, and alteration of ECM homeostasis . Although in wound-healing studies it has described an antifibrotic role for macrophages due to their participation in the resolution of the deposited ECM through phagocytosis , many short-term studies relate the number of infiltrated macrophages with the extent of fibrosis and kidney dysfunction [reviewed in ], supporting an etiological role of these cells in the pathogenesis of renal damage. Moreover, attenuated accumulation of macrophages in experimental obstructive nephropathy is accompanied by enhanced renal interstitial fibrosis and profibrotic activity . However, longer-term studies reveal a reciprocal relationship between these two parameters and raise some questions about the function of infiltrating cells . Thus, probably machrophages play a dual effect, with a short-tem profibrotic effect, and a long-term healing effect.
The interstitial wound in the fibrotic kidney is formed by excessive deposition of constituents of the interstitial matrix (e.g. collagen I, III, V, VII, XV, fibronectin), components restricted to tubular basement membranes in normal conditions (collagen IV and laminin), and de novo synthesized proteins (tenascin, certain fibronectin isoforms and laminin chains) . Fibronectin, with chemoattractant and adhesive properties for the recruitment of fibroblasts and the deposition of other ECM components , is one of the first ECM proteins to accumulate as a response to the initial damage. Fibroblasts, myofibroblasts, macrophages, mesangial and tubular cells are sources of fibronectin in inflammation and fibrogenesis [95, 96]. Other upregulated components in the interstitium of fibrotic kidneys are hialuronic acid [97, 98], secreted protein acidic and rich in cysteine (SPARC; 98), thrombospondin [99, 100], decorin and biglycan [101, 102] (see table 2 and figure 3).
Certain types of CKD are caused by a marked alteration of renal collagenase activity with small or no changes in collagen synthesis. Renal fibrosis in mice with ureteral obstruction is also the result of decreased collagenolytic activity . In damaged kidneys, upregulation of TGF-β activation also contributes to override the natural ECM homeostatic equilibrium by downregulating the expression of determined MMPs and activating the expression of the MMP-inhibitor plasminogen activator inhibitor 1 (PAI-1; 51,104-106). Also TIMP-1, an endogenous tissue inhibitor of MMPs, is actively synthesized by renal cells in progressive CKD , and its expression is stimulated by TGF-β, TGF-α, epithelial growth factor (EGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF-α), interleukins 1 and -6, oncostatin M, endotoxin, and thrombin . However its role is controversial because TIMP-1 deficient mice show no significant differences in interstitial fibrosis during induced renal damage [87, 108].
Progressive tissue destruction
Tubular atrophy is a histological feature of progressive CKD . Excessive accumulation of ECM, together with expansion and inflammation of the extracellular space, has destructive effects on renal parenchyma and renal function . Loss of tubular cells occurs during the destructive phase as a consequence of apoptosis, persistent EMT (with an undetermined contribution), and interstitial scarring . At this stage, unbalanced fibrogenesis may also contribute to tubular cell death. Interstitial fibrosis impairs oxygen supply to tubular and interstitial cells, which leads or sensitizes to apoptosis . A relevant apoptosis effector in CKD is the Fas-initiated extrinsic pathway . In fact, attenuated expression of the apoptosis-mediated receptor Fas and the endogenous agonist Fas ligand (FasL) reduced tubular epithelial cell apoptosis in an in vivo model of diabetic nephropathy . However, in normal circumstances, many epithelial cell types, including renal tubular epithelial cells, are refractory to Fas stimulation-induced apoptosis . Inadequate Fas clustering and altered equilibrium of pro- and anti-apoptotic intracellular modulators may explain the lack of sensitivity to Fas [115, 116]. Specifically, signaling at the level of the death-induced signaling complex (DISC) formed around Fas upon receptor stimulation is due to basal expression of Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein (FLIP), an endogenous inhibitor of DISC . FLIP antisense or cycloheximide treatment, which also drastically reduces cellular levels of FLIP, make refractory fibroblasts to undergo apoptosis upon Fas stimulation. Accordingly, priming stimulation is necessary to make epithelial tubule cells sensitive to Fas-mediated apoptosis, as it occurs in CKD.
TGF-β intervenes in tubule apoptosis in vivo as demonstrated by the reduced apoptosis after treatment with an anti TGF-β1 antibody in rats with ureteral obstruction [86–118]. Given its central role in CKD , TGF-β poses a good candidate for priming tubular cells to Fas-induced apoptosis. Another candidate for mediating sensitization to Fas-induced apoptosis is angiotensin II. In vivo, inhibition of angiotensin II results in a strong amelioration of CKD-associated damage, including tubular epithelial cell apoptosis . In vitro, angiotensin II induces apoptosis in rat proximal tubular epithelial cells, and this effect is mediated through the synthesis of TGF-β followed by the transcription of the cell death genes Fas and FasL . In this setting, treatment of tubular epithelial cells with an anti TGF-β neutralizing antibody partially inhibits, while an anti FasL antibody strongly inhibits angiotensin II-induced apoptosis. IL-1 and hypoxia also induce an upregulation of Fas expression in tubule cells [121–123]. Very recently, it has been shown that confined tubular overexpression of TGF-β in mice produces massive proliferation of peritubular cells, widespread fibrosis and focal nephron loss associated to tubular cell dedifferentiation and autophagy , although the role of autophagy in tubule cell death needs to be further explored.
The interplay of these and other factors need to be further explored in order to understand the onset of apoptosis in tubular cells during CKD . Furthermore, angiotensin II is a regulator of renal cell function, including tubular cells under physiological conditions . This duality could be related to the fact that cell-to-cell and ECM-to-cell interactions, as well as specific humoral determinants present in different pathophysiological circumstances condition the effect of angiotensin II on cell fate and function. For example, the collagen discoidin domain receptor I is involved in survival of tubular Madin-Darby canine kidney (MDCK) cells . As such, an excessive collagen I and fibronectin deposition may alter cell sensitivity to apoptosis . A number of circumstances must hypothetically be present to let angiotensin II (and other mediators) induce apoptosis in vivo, such as a determined humoral coactivating context, and ECM homeostatic disruption caused by fibrogenesis. Probably, persistence of angiotensin II contributes to generate these permissive phenotypes. Finally, ischemia may also directly induce or sensitize tubular epithelial cells to apoptosis and necrosis [129, 130], or indirectly through promotion of fibrogenesis. In fact, culture of tubular cells in hypoxic conditions reduces MMP activity and increases total collagen content . Also, in experimental CKD, hypoxia-inducible factor (HIF) has been shown to mediate hypoxia-induced fibrosis [132, 133]. Fibrosis also affects the diseased renal vascular tree by reducing the lumen of individual vessels and peritubular capillary cross sectional area . Figure 3 depicts a prototypical tubulointerstitial situation showing the most important extracellular mediators of key pathological events.
Glomerulopathies are renal disorders affecting glomerular structure and function. Primary glomerulopathies encompass inflammatory glomerular diseases (glomerulonephritis) and non-inflammatory glomerulopathies . In addition, secondary glomerulopathies result from primary tubulointerstitial and renovascular diseases, which contribute to the progression of the damage . Primary inflammatory and non-inflammatory conditions give rise to the nephritic and nephrotic syndromes, respectively . Diabetes, hypertension and glomerulonephritis represent the major causes of chronic renal failure in glomerular diseases .
Inflammatory glomerular diseases are due to (i) systemic and renal infections; (ii) focal and segmental glomerulonephritis; (iii) glomerular basement membrane damage resulting from immune deposits in the capillary wall (lupus nephritis, membranoproliferative glomerulonephritis), accumulation of IgA complexes in the glomerulus (IgA nephropathy) and others; and (iv) vasculitic glomerulonephritis. Glomerulonephritis involves glomerular inflammation. Cellular and humoral immune responses participate in this injury, which involve circulating and in situ-formed immunocomplexes , and complement pathways , which tend to accumulate in the components of the filtration barrier and to disrupt its structure. A major consequence of glomerulonephritis is the nephritic syndrome characterized by hematuria and proteinuria (due to alterations in the glomerular filtration barrier) and by reduced glomerular filtration, oliguria and hypertension due to fluid retention . Additional characteristic hallmarks of glomerulonephritis include the activation and proliferation of mesangial cells  and endothelial cells , which contribute to the fibrosis and sclerotic scar lesions commonly observed in damaged glomeruli.
Non-inflammatory glomerular diseases comprise a repertoire of metabolic and systemic diseases that chemically or mechanically damage the glomerulus, such as diabetes and hypertension, toxins and neoplasias. Non-inflammatory glomerular diseases also include idiopathic membranous nephropathy because, although it results from immune injury to the podocyte, glomerular inflammation is not conspicuous, at least initially. Diabetes is the leading cause of CKD and ESRD in developed countries, resulting in 20-40% of all patients developing ESRD . Persistent hypertension is another important trigger of non-inflammatory glomerular disease, caused by pathologic remodeling of the capillary tuft as a response of an increased perfusion pressure and physical stress. Although the autoregulatory capacity of renal blood flow effectively protects the kidneys against hypertension, protection is mostly but not completely effective, and autoregulation partially fades away in a slow but progressive manner . The major clinical syndrome produced by non-inflammatory glomerulopathies is the nephrotic syndrome. It presents with severe proteinuria (> 3 g/day), hypoalbuminemia, oedema, hyperlipidemia and lipiduria , with reduced or even normal glomerular filtration. Contrarily to the nephritic syndrome, the nephrotic syndrome courses without hematuria. Yet, it must be emphasized that even non-inflammatory glomerulopathies course with renal inflammation, which is a key mechanism of progression and an important target for therapeutics . The difference with inflammatory glomerulopathies is that inflammation is secondary to the injury inflicted by the initiating cause.
Histopathological alterations and consequences of the glomerular damage
Glomerular pathogenetic mechanisms are as diverse as types of primary glomerulopathies. Dependent on the aetiology, specific glomerular diseases course with a specific mix of renal histopathological findings or patterns, including focal and segmental sclerosis, diffuse sclerosis, mesangial, membranous or endocapillary proliferation, membranous alterations and immune deposits, crescent formations, thrombotic microangiopathy, vasculitis and others. A determined glomerular disease may evolve through different histopathological patterns. As an example, diabetic nephropathy has been recently classified in 4 types: (i) Class I, characterized by isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy; (ii) Class II, in which mild (IIa) or severe (IIb) mesangial expansion is observed without nodular sclerosis, or global glomerulosclerosis in more than 50% of glomeruli. (iii) Class III, when nodular sclerosis or Kimmelstiel-Wilson lesions are present in at least one glomerulus with nodular increase in mesangial matrix, without changes described in class IV; and (iv) Class IV or advanced diabetic glomerulosclerosis, characterized by the presence of more than 50% of the glomeruli with global glomerulosclerosis, and further clinical or pathologic evidence ascribing sclerosis to diabetic nephropathy .
Glomerular endothelial cells are also primary sites of injury resulting in glomerulopathies and CKD. They will be addressed in section 4, along with other renovascular diseases. Besides thrombotic microangiopathy, glomerulo-vascular diseases include atherosclerotic microembolia, small vessel vasculitis, diabetic nephropathy, membranoproliferative and post-infectious glomerulonephritis, lupus nephritis and the inherited disease familial hemolytic uremic syndrome. In addition, the hemodynamic damage is an important component of glomerulosclerosis and progressive glomerular injury in most forms of CKD. Hyperfiltration, glomerular hypertension, glomerular distention and inflammation occurring after the initial insult cause diverse glomerular alterations that activate, and even damage, mesangial and endothelial cells [; see also section 5].
Glomerular ECM deposition evolves in patients with glomerulonephritis as the disease progresses . As in normal kidneys, no interstitial collagen I and III are detected in patients with mild glomerulonephritic damage . Progressive renal damage correlates with increasing presence of collagen IV and VI, laminin and fibronectin in the mesangium. Finally, in later stages of glomerulonephritis, the amount of collagen IV, laminin and fibronectin gradually decreases, while focal expression of collagen I and III increases. Glomerular cell apoptosis also occurs in parallel to sclerosis, and ECM progressively scars the spaces left by dead cells .
Inflammation plays a pivotal role in the progression of many, if not all, forms of CKD. In the glomerulus, inflammation exerts different effects that amplify the damage and directly contribute to the reduction in glomerular filtration (see section 3.2.). Initially, inflammation is probably activated as a repair mechanism upon cellular and tissue injury. However, undetermined pathological circumstances skew persistent inflammation into a vicious circle of destruction and progression. In fact, inflammation activates many renal cell types to produce cytokines, which directly damage renal cells and intensify inflammation.
Cells and molecular mediators involved
Mesangial cells are contractile glomerular pericytes that play a major role in the regulation of renal blood flow and GFR. They also have a pivotal participation in the genesis of chronic glomerular diseases. Mesangial cell proliferation is a common feature during the initial phase of many chronic glomerular diseases, including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy . Numerous experimental models of glomerular damage have reported that proliferation of mesangial cells frequently precedes and is associated with ECM deposition in the mesangium and, therefore, to fibrosis and glomerulosclerosis. In fact, reduction of mesangial cell proliferation in glomerular disease models ameliorates ECM deposition, fibrosis and glomerulosclerosis . Thus, proliferating mesangial cells are considered to be a central source of ECM production in both focal and diffuse glomerulosclerosis [155, 156].
The fibrotic mechanism of renal damage in glomerulopathies represents a final common pathway with the initial glomerular insult starting a cascade of events that include an early inflammatory phase followed by a fibrogenic response in the glomerular and the tubulointerstitial compartments of the kidneys . Several cytokines, growth factors and complement proteins, through the activation of nuclear factor-κB (NF-κB)-related pathways, initiate the damage stimulating the mesangial cells to release chemotactic factors . As previously reported, angiotensin II is one of the main effectors implicated in resident cell activation in pathological kidney . Infusion of angiotensin II induces a marked renal damage in glomeruli, tubulointerstitium and vascular system, associated with cell proliferation, leukocyte infiltration, interstitial fibrosis and modulation of mesangial cell phenotype . In the short-term, angiotensin II acting on mesangial cells induces an increase of cytosolic calcium and inositol phosphate, prostaglandin synthesis and cellular contraction and long-term alterations such as proliferation, hypertrophy and ECM production . These effects are mediated by autocrine factors released upon angiotensin II action, such as TGF-β1 [86, 136, 160]. TGF-β induces mesangial cell proliferation directly and through the concourse of PDGF . PDGF appears to be an important mediator of mesangial proliferation, and HGF counteracts PDGF actions . Several pathogenic molecules have been additionally related to the development of glomerulosclerosis, including endothelin  and reactive oxygen species  that have also been implicated in angiotensin II-induced hypertrophy of mesangial cells .
Renal vasoconstriction that diminishes renal blood flow with two consequences: on the one hand it diminishes glomerular filtration, and on the other, it may lead to oxygen deficit and hypoxia in determined circumstances. Hypoxia sensitizes cells to cell death and activates the release of HIF, which promotes fibrosis [131–133]. Besides, hypoxia limits the cell's ATP reserve and thus it may change the cell death phenotype to necrosis , which in turn further activates the immune response. Vasoconstriction might be the result of endothelial dysfunction and oxidative stress [178–180], and also of release of contracting factors such as endothelin-1 and platelet activating factor (PAF) by endothelial and mesangial cells, and podocytes [181–184].
Proliferating parietal epithelial cells (PECs) of Bowman's capsule have been involved in the development of FSGS, and in extracapillary proliferation. Long considered passive bystanders in CKD, in recent years several studies have shown that PECs proliferate and produce ECM components contributing to fibrosis, adhesions of glomerular capillary to Bowman's capsule [188, 189], and glomerular collapse, in different glomerular diseases. In addition, PECs can become activated and express many growth factors, chemokines, cytokines, and their receptors [reviewed in ].
Finally, podocytes have progressively gained central attention in glomerulopathies and are considered to have a central role in the pathological process, as a result of both genetic and acquired alterations. Loss of podocytes, which lack the ability of postnatal proliferation, has been implicated in the progression of glomerular diseases to glomerulosclerosis . Podocytes are specialized pericytes placed around the glomerular capillaries, which contribute to the special characteristics of the glomerular filtration barrier [148, 192]. Human acquired proteinuric glomerulopathies, such as diabetic nephropathy, minimal-change nephrotic syndrome (MCNS), FSGS, and membranous nephropathy (MN), commonly exhibit foot process effacement of podocytes and loss of slit diaphragms in electron microscopy; these glomerulopathies therefore are considered as podocyte injury diseases (podocytopathies) [148, 193]. Several experimental models, such as rat puromycin aminonucleoside (PAN) nephropathy and mouse adriamycin (ADR) nephropathy that develop massive proteinuria resembling human minimal change disease, have provided insights into the cellular and intracellular mechanisms of podocyte injury disease.
Podocyte dysfunction leads to progressive renal insufficiency. First, podocyte damage causes proteinuria. Sustained proteinuria gives rise to tubulointerstitial injury, eventually leading to renal failure . Second, podocyte injury impairs mesangial structure and function. In anti-Thy-1 glomerulonephritis, the induction of minor podocyte injury with PAN pretreatment results in an irreversible mesangial alteration . In addition, cysteine-rich protein 61 (Cyr61), a potent angiogenic protein that belongs to the CCN family of matrix-associated secreted protein family, is expressed in podocytes and upregulated in anti-Thy-1 glomerulonephritis . Cyr61 inhibits mesangial cell migration, suggesting that Cyr61 may play a modulatory role in limiting mesangial activation. Thus, podocytes may secrete various humoral factors that regulate mesangial structure and function, and their reduction could result in impaired mesangial function, mesangial proliferation and matrix expansion. For example, angiotensin II and high glucose exposure increase podocyte production of TGF-β1  and VEGF , both of which are known to affect mesangial cells . Third, podocyte loss or detachment from the glomerular basement membrane leads to glomerulosclerosis . In human diabetic nephropathy and IgA nephropathy, decreased podocyte number correlates significantly with poor prognosis [201, 202]. These data suggest that podocyte injury is critical not only in podocyte-specific diseases such as MCNS and FSGS but also in podocyte-nonspecific diseases such as IgA and diabetic nephropathy.
Renovascular diseases comprise a group of progressive conditions involving renal dysfunction and renal damage derived from the narrowing or blockage of the renal blood vessels. According to the U.S. Renal Data System , about one third of all ESRD cases were related to renovascular diseases. Renovascular diseases usually appear as microangiopathies, although renal artery occlusion, renal vein thrombosis, and renal atheroembolism are also potential causes. The term is most often used to describe diseases affecting the renal arteries, because blockage of the renal veins is not very common. Renovascular alterations affect the main renal arteries and their branches (stenosis) or microvessels (thromboembolic microangiopathy) and lead to CKD. Atherosclerosis induces 70-90% of cases of renal stenosis and is the predominant lesion detected in patients >50 years of age [204, 205], whereas most remaining cases are caused by fibromuscular dysplasia. The latter is a group of idiopathic fibrotic conditions affecting especially the media, but also the intima and the adventitial layers of small vessels, which is more frequent in middle-aged women. Unusual causes of stenosis are external pressure (e.g. exerted by a tumor), partial occlusion at the suture level after renal transplant, as well as nephroangiosclerosis (hypertensive injury), diabetic nephropathy (in small vessels), renal thromboembolic disease, atheroembolic renal disease, aortorenal dissection, renal artery vasculitis, trauma, neurofibromatosis, thromboangiitis obliterans and scleroderma [206, 207]. CKD is a probable outcome, although stenotic hypoperfusion is not synonymous with renal disease. Surprisingly, stenosis caused by fibromuscular dysplasia rarely provokes renal damage, despite inducing intrarenal hemodynamic changes and activating pressor mechanisms as well. On the contrary, atherosclerotic stenosis more often leads to CKD. Even moderate stenosis can (more rarely) give rise to CKD. The likelihood of developing CKD associated with atherosclerotic stenosis escalates with the severity and persistence of the occlusion and with the presence of comorbid factors .
As explained in the next paragraphs, renovascular diseases may alter renal function and structure directly through (i) atherosclerosis-initiated renal oxidative stress, endothelial dysfunction and inflammation leading to fibrosis and reduced filtration; (ii) creating hypoperfusion and ischemic scenarios compromising renal blood flow, and tubular and glomerular function; and (iii) indirectly, through the onset of hypertension.
Atherosclerosis and renal injury
Increased production of ROS in pathological situations such as hypertension and atherosclerosis is frequently mediated by activation of the renin-angiotensin system and NAD(P)H oxidase [211–213]. As Chade et al.  showed that systemic plasma renin activity was not elevated in an in vivo experimental model of renovascular disease, the intrarenal renin-angiotensin system seems to be activated within the stenotic kidney. The angiotensin II-induced ROS generation through activation of NAD(P)H oxidase seems to involve a feed-forward mechanism inducing a prolonged production of ROS . Chronic effects of oxidative stress play a relevant role in the pathogenesis of renal injury in renovascular disease , and oxidative stress clearly contributes to renovascular-induced hypertension . ROS may induce vasoconstriction and modulate renal microvascular function , contributing to the enhanced renal vascular tone and sensitivity induced by other vasoconstrictors such as angiotensin II and endothelin-1. Furthermore, superoxide anion and nitric oxide (NO) may also react with each other, which decreases NO availability and impairs intrarenal vascular and glomerular function due to the formation of peroxynitrite [213, 216]. Finally, antioxidants have shown to prevent the renal damage and dysfunction induced by renal artery obstruction and atherosclerosis . All these facts suggest that increased oxidative stress is involved, at least partially, in the impaired endothelium-dependent vasodilatation observed in patients with renovascular hypertension.
Renal injury due to hypoperfusion and ischemia
Severe occlusions decreasing over a 60% of renal flow, lead to a reduction of renal perfusion pressure under the autoregulatory range (< 70-85 mmHg). Renal hypoperfusion appears only when renal perfusion pressure falls below the autoregulatory range, and thus renal blood flow declines. It is estimated that a 70-80% of the luminal area of the renal artery must be occluded for hypoperfusion to occur, which is termed "critical stenosis" . This condition induces a generalized tissue hypoperfusion (sometimes referred to as ischemia) and excretory dysfunction, which may evolve to fibrosis (frequently to secondary FSGS) and CKD. Localized or spread thromboembolic microangiopathy may also cause focal or generalized true ischemic scenarios, which may be the consequence of systemic atherosclerotic disease, or may be indirectly potentiated by it through main renal artery atherosclerotic stenosis. Still, a severe diminution of renal blood flow does not necessarily cause an injuring ischemia, but it may merely lead to a reversible, hibernating-like functional state and in some cases to renal damage . It must be born in mind that just a mere 10% of total oxygen passing through the kidney is used for its metabolic needs . In this situation, pressor mechanisms become invariably activated which raise systemic blood pressure and, consequently, renal perfusion pressure to achieve water and electrolyte balance (see 4.3.). Hypertension aggravates the renal stenosis outcome . In fact, a complex relationship has been described among renal artery stenosis, hypertension and CKD .
Severe renal hypoperfusion leads to microvascular rarefaction (MR) and deficient vascular endothelium growth factor (VEGF) production and focal or spread ischemia . MR seems to play a significant role in renovascular disease, because exogenous administration of VEGF prevents MV and renal dysfunction . Ischemia also is recognized as a strong injuring and fibrogenic stimulus, but the mechanisms leading to CKD are poorly understood . HIF, which is a pro-angiogenic and protective mediator in vivo released by ischemic cells, has been demonstrated to promote renal fibrosis in chronic pathological circumstances . Finally, renal hypoperfusion has been linked to tubular injury . Decreased O2 and glucose supply limit ATP production, which leads or predisposes cells to dying [224–226]. Hypoxia also activates inducible nitric oxide synthase (iNOS) expression, which produces oxidative stress, inhibits ATP synthesis and activates apoptosis .
Hypertension is a prospective inducer of renal damage in stenotic kidneys . Hypertensive nephropathy is a glomerulopathy initiated by the increase in intraglomeular pressure, which activates and damages glomerular cells, including mesangial and epithelial cells and podocytes. These cells produce proinflammatory and vasoactive mediators that contribute to cell damage and fibrosis, reduce renal blood flow, Kf, and glomerular filtration (as described in general for glomerulopathies in section 3, and specifically in 143; and depicted in figure 6). Initially, hypertension-induced stress activates the local RAS at the glomerular level. As in many other cardiovascular pathological situations, local RAS has been decisively implicated in tissue alteration and remodelling. Renal TGF-β, NF-κB and other cytokines are upregulated in a model of hypercholesterolemic renovascular CKD , and also in a model of aortic coarctation between both renal arteries, which pathologically resembles unilateral stenosis [230, 231]. They might mediate the inflammatory, fibrotic and apoptotic events, as described generally for glomerular and tubular diseases .
In unilateral stenosis, the obstructed kidney responds as in bilateral stenosis with renin release, angiotensin II production and hypertension. In unilateral stenosis, maintenance of hypertension is dependent on a constantly activated RAS. High levels of circulating and renal angiotensin II become increased , which probably reset the pressure-natriuresis-diuresis mechanism in the non stenotic kidney to higher levels of pressure, so that water and electrolyte balance is achieved at the new pressure. In fact, RAS blockers (e.g. angiotensin converting enzyme inhibitors, ACEIs) inhibit both the appearance and maintenance of hypertension in this model . It is noteworthy that angiotensin II is capable of sustaining hypertension in the long term, as demonstrated by the experimental rat hypertension model induced by constant administration of angiotensin II . In unilateral stenosis (and associated experimental models, e.g. the Goldblatt experimental model of unilateral stenosis, "two-kidney, one-clip" -2K1C-, and the aortic coarctation between the renal arteries) the non stenotic kidney also undergoes structural alterations [230, 231], probably as a consequence of the developed hypertension, or as a result of the systemic or local humoral alterations switched as a compensatory response. In fact, TGF-β expression is upregulated as well in the contralateral kidney by 3-5 weeks after stenosis in 2K1C .
Merging mechanisms of progression
Mechanisms traditionally suggested to connect primary glomerulopathies with the subsequent pathological recruitment of the tubulointerstitial space are : (i) an increased reabsorption of proteins in the proximal tubules, resulting from glomerular hyperfiltration associated with glomerular damage. An increased tubular reabsorbtion of proteins activates the production of cytokines by tubular cells, which, in turn, promotes the infiltration of immune cells and the activation of an immune-inflammatory response (238; and see the section "Historical view" in 2). Abnormally filtered bioactive macromolecules interact with proximal tubular epithelial cells, activating signalling pathways that include NFkB [239, 240]. The megalin-cubilin complex mediates the uptake of several proteins, including albumin, into proximal tubular epithelial cells. Megalin might also initiate or participate in intracellular signalling linking abnormal albuminuria with proinflammatory and profibrotic signaling . The neonatal Fc receptor and CD36 could also play a role. Furthermore, addition of albumin or transferrin to tubule cells reduces their ability to bind factor H and counteract complement activation . Albumin can also be a source of potentially antigenic peptides upon processing by renal dendritic cells . Indeed, proteinuria is not only a marker of disease, but also an effector of nephropathy. Proteinuria correlates with disease progression, and pharmacological prevention of proteinuria also correlates with progression slowing ; (ii) direct encroachment of extracapillary lesions from the glomerulus to the tubule ; (iii) recurring acute glomerular insults (as by toxics, metals, drugs, infections, etc.) which perpetuate the production of growth factors and chemokines involved in tubular damage ; (iv) postglomerular malperfusion derived from the degradation, collapse or narrowing of glomerular capillaries, resulting in tubular hypoxia ; (v) formation of paraglomerular exudates containing profibrotic factors, ECM, basement membrane material and tissue debris from epithelial cells and podocytes, which reach the tubular structures through interstitial routes and initiate an injury process leading to tubulointerstitial fibrosis and tubule degeneration that, in some instances, may lead to the physical separation of the glomerulus and the tubule, and the formation of a glomerular cyst . Sclerotic nuclei begin at glomerular adhesions formed by a glomerular capillary to Bowman's capsule at a podocyte deprived basement membrane point, which lead to the formation of a paraglomerular space (PGS). PGS contains ectopic filtrate and capillary tuft debris. The PGS content is proposed to play a significant role in the initiation of damage and in the connection of glomerular and tubular diseases. It must be pointed out that increasing evidence suggests that even in traditionally considered glomerulopathies, such as diabetic nephropathy, some degree of tubular damage occurs before the first evidence of glomerular injury can be detected [243–247]. This may eventually force us to reshape our conceptual separation of glomerular and tubular diseases into a more integrative view .
Regardless of cause, as a consequence of the increasing renal dysfunction, compensatory responses are activated, which may also engage in the progressive pathological vortex. These responses include hypertension and peripheral or renal sympathetic hyperactivity , which are commonly observed in CKD patients. Indeed, baroreceptor-mediated renal sympathetic hyperactivity has been recently linked to the inception and maintenance of hypertension . Figure 8 compiles the pathological mechanisms connecting tubular and glomerular damage, which set the basis of a common renal pattern of disease during the progression of CKD.
Conclusions, clinical implications and perspectives
This review summarizes the key pathophysiological events of CKDs compromising renal excretory function, at the organism, tissue, cell and molecular levels. CKDs may be originated in the glomeruli, in the tubuli or in the renal vessels. Most of the diseases in each of these groups have specific, but also common pathophysiological characteristics resulting from increasingly understood mechanisms of action. Moreover, all these diseases, regardless of aetiology, eventually affect all parts of the nephron and enter an irreversible course that may compromise the patient's life. In addition, as the disease progresses, a more uniform pathophysiological pattern installs characterized by increasing fibrosis, inflammation, nephron loss and parenchymal scarring. Present treatments of CKD are only reasonably effective at slowing progression. They are installed substantially after irreversibility ensues, mostly because clear pathological signs only arise after over 50% of the nephrons are functionally nulled. In these conditions, the earliest possible diagnosis is critical for prognosis. Moreover, the identification of new biomarkers and technologies to move progressively earlier the moment of diagnosis is an active area of research.
The follow-up of CKD patients shows that the overall death rate increases as kidney function decreases, and the mortality in patients with ESRD remains 10-20 times higher than that in the general population. At present there is no cure for CKD; the natural course of the disease is to progress towards ESRD and death, unless dialysis or transplant is implemented. The focus in recent years has thus shifted to optimizing the care of these patients during the phase of CKD, and to slow progression with the aim of avoiding the necessity of renal replacement therapy during the patient's lifespan. In many cases, it is possible to slow the progression of CKD to ESRD if kidney disease is diagnosed and treated in its earlier stages, mainly with renin-angiotensin system blockers, although other drugs are under development based on known mechanisms of progression [143, 249]. Thus, early CKD identification has potentially enormous socioeconomic and medical benefits. Still, the development of earlier diagnostic tools and better drugs for preventing and, ideally, reversing renal damage and restoring renal function needs a better knowledge of pathophysiological mechanisms of CKD genesis and progression. In this sense, reversal of CKD in the clinical setting is still an unmet goal. However, promising results have been obtained in some studies with experimental models of renal fibrosis, for instance using BMP-7 as a therapeutic agent [250, 251].
Yet, a valuable and potentially useful piece of knowledge for the clinical handling of CKD is still in the horizon; namely understanding how and why an initial or persistent insult to the kidney is not repaired but, on the contrary, leads to an irreversible scenario of self destruction, which even becomes independent from the cause. This no-return point in the fate of injured kidneys probably holds the key to a conceptual therapeutic drift from slowing progression towards regression and, along with a sufficiently early diagnosis, prevention entering the vicious circle of deterioration. As it has been suggested that an imbalance of pro-fibrotic and anti-fibrotic cytokines is in the core of the no-return point , it would be helpful to focus research efforts on this key aspect of CKD, as a way to gain true control over this disease.
- Mitch WE, Walser M, Buffington GA, Lemann J: A simple method of stimating progression of chronic renal failure. Lancet. 1976, 2: 1326-1328. 10.1016/S0140-6736(76)91974-7.PubMedGoogle Scholar
- Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest. 2006, 116: 288-296. 10.1172/JCI27699.PubMed CentralPubMedGoogle Scholar
- Chin C: Renal failure: Pharmacologic issues. Pharmacy Practice. 2002, 1-8.Google Scholar
- Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan G, National Kidney Foundation: National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003, 139: 137-147.PubMedGoogle Scholar
- Snively CS, Gutierrez C: Chronic kidney disease: Prevention and treatment of chronic complications. American Family Physician. 2004, 70: 1921-1928.PubMedGoogle Scholar
- Snyder S, Pendergraph B: Detection and evaluation of chronic kidney disease. American Family Physician. 2005, 72: 1723-1732.PubMedGoogle Scholar
- Feig DI: Uric acid: a novel mediator and marker of risk in chronic kidney disease?. Curr Opin Nephrol Hypertens. 2009, 18: 526-530. 10.1097/MNH.0b013e328330d9d0.PubMed CentralPubMedGoogle Scholar
- Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, Arroyo D, Luño J: Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010, 5: 1388-1393. 10.2215/CJN.01580210.PubMed CentralPubMedGoogle Scholar
- Bellomo G, Venanzi S, Verdura C, Saronio P, Esposito A, Timio M: Association of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis. 2010, 56: 264-272. 10.1053/j.ajkd.2010.01.019.PubMedGoogle Scholar
- Brenner BM: Nephron adaptation to renal injury or ablation. Am J Physiol. 1985, 249: F324-337. (1985).PubMedGoogle Scholar
- Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, Steffes MW: American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004, 7 (Suppl 1): S79-83.Google Scholar
- U.S. Renal Data System, USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009.Google Scholar
- Brosnahan G, Fraer M: Chronic kidney disease: whom to screen and how to treat, part 1: definition, epidemiology, and laboratory testing. South Med J. 2010, 103: 140-146.PubMedGoogle Scholar
- Stengel B, Tarver-Carr ME, Powe NR, Eberhardt MS, Brancati FL: Lifestyle factors, obesity and the risk of chronic kidney disease. Epidemiology. 2003, 14: 479-487.PubMedGoogle Scholar
- Hsu CY, Mc Culloch ChE, Iribarren C, Darbinian J, Go AS: Body mass index and risk for end-stage renal disease. Ann Intern Med. 2006, 144: 21-28.PubMedGoogle Scholar
- Ejerblad E, Foerd M, Lindblad P, Fryzek J, McLaughlin JK, Nyrén O: Obesity and risk for chronic renal failure. J Am Soc Nephrol. 2006, 17: 1695-1702. 10.1681/ASN.2005060638.PubMedGoogle Scholar
- Ritz E: Metabolic syndrome and kidney disease. Blood Purif. 2008, 26: 59-62. 10.1159/000110566.PubMedGoogle Scholar
- Hall JE, Crook ED, Jones DW, Wofford MR, Dubbert PM: Mechanisms of obesity-associated cardiovascular and renal disease. Am J Medical Sciences. 2002, 324: 127-137. 10.1097/00000441-200209000-00003.Google Scholar
- Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med. 2004, 140: 167-174.PubMedGoogle Scholar
- Ting SM, Nair H, Ching I, Taheri S, Dasgupta I: Overweight, obesity and chronic kidney disease. Nephron Clin Pract. 2009, 112: c121-127. 10.1159/000214206.PubMedGoogle Scholar
- Faronato PP, Maioli M, Tonolo G, Brocco E, Noventa F, Piarulli F, Abaterusso C, Modena F, de Bigontina G, Velussi M, Inchiostro S, Santeusanio F, Bueti A, Nosadini R: Clusterin of albumin excretion rate abnormalities in Caucassian patients with NIDDM. The Italian NIDDM nephropathy study group. Diabetologia. 1997, 40: 816-823. 10.1007/s001250050754.PubMedGoogle Scholar
- Satko SG, Freedman BI: The importance of family history on the development of renal disease. Curr Opin Nephrol Hypertens. 2004, 13: 337-341. 10.1097/00041552-200405000-00012.PubMedGoogle Scholar
- Gohda T, Tanimoto M, Watanabe-Yamada K, Matsumoto M, Kaneko S, Hagiwara S, Shiina K, Shike T, Funabiki K, Tomino Y: Genetic susceptibility to type 2 diabetic nephropathy in human and animal models. Nephrology (Carlton). 2005, 10 (Suppl): S22-25. 10.1111/j.1440-1797.2005.00452.x.Google Scholar
- Satko SG, Freedman BI, Moossavi S: Genetic factors in end-stage renal disease. Kidney Int Suppl. 2005, 94: S46-49. 10.1111/j.1523-1755.2005.09411.x.PubMedGoogle Scholar
- Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, Coresh J, Patterson N, Tandon A, Powe NR, Fink NE, Sadler JH, Weir MR, Abboud HE, Adler SG, Divers J, Iyengar SK, Freedman BI, Kimmel PL, Knowler WC, Kohn OF, Kramp K, Leehey DJ, Nicholas SB, Pahl MV, Schelling JR, Sedor JR, Thornley-Brown D, Winkler CA, Smith MW, Parekh RS: Family Investigation of Nephropathy and Diabetes Research Group. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet. 2008, 40: 1185-1192. 10.1038/ng.232.PubMedGoogle Scholar
- Freedman BI, Hicks PJ, Bostrom MA, Cunningham ME, Liu Y, Divers J, Kopp JB, Winkler CA, Nelson GW, Langefeld CD, Bowden DW: Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans. Kidney Int. 2009, 75: 736-745. 10.1038/ki.2008.701.PubMed CentralPubMedGoogle Scholar
- Divers J, Freedman BI: Susceptibility genes in common complex kidney disease. Curr Opin Nephrol Hypertens. 2010, 19: 79-84. 10.1097/MNH.0b013e3283331e50.PubMed CentralPubMedGoogle Scholar
- Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR: Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010, 329: 841-845. 10.1126/science.1193032.PubMed CentralPubMedGoogle Scholar
- Tsukaguchi H, Sudhakar A, Le TC, Nguyen T, Yao J, Schwimmer JA, Schachter AD, Poch E, Abreu PF, Appel GB, Pereira AB, Kalluri R, Pollak MR: NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest. 2002, 110: 1659-1666.PubMed CentralPubMedGoogle Scholar
- Franceschini N, North KE, Kopp JB, McKenzie L, Winkler C: NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review. Genet Med. 2006, 8: 63-75. 10.1097/01.gim.0000200947.09626.1c.PubMedGoogle Scholar
- Brown EJ, Schlöndorff JS, Becker DJ, Tsukaguchi H, Tonna SJ, Uscinski AL, Higgs HN, Henderson JM, Pollak MR: Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet. 2010, 42: 72-76. 10.1038/ng.505.PubMed CentralPubMedGoogle Scholar
- Mukerji N, Damodaran TV, Winn MP: TRPC6 and FSGS: the latest TRP channelopathy. Biochim Biophys Acta. 2007, 1772: 859-868.PubMedGoogle Scholar
- Korstanje R, DiPetrillo K: Unraveling the genetics of chronic kidney disease using animal models. Am J Physiol Renal Physiol. 2004, 287: F347-352. 10.1152/ajprenal.00159.2004.PubMedGoogle Scholar
- Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC: Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes. 1998, 47: 821-830. 10.2337/diabetes.47.5.821.PubMedGoogle Scholar
- DeWan AT, Arnett DK, Atwood LD, Province MA, Lewis CE, Hunt SC, Eckfeldt J: A genome scan for renal function among hypertensives: the HyperGEN study. Am J Hum Genet. 2001, 68: 136-144. 10.1086/316927.PubMed CentralPubMedGoogle Scholar
- Perez-Luque E, Malacara JM, Olivo-Diaz A, Aláez C, Debaz H, Vázquez-Garcia M, Garay ME, Nava LE, Burguete A, Gorodezky C: Contribution of HLA class II genes to end stage renal disease in mexican patients with type 2 diabetes mellitus. Hum Immunol. 2000, 61: 1031-1038. 10.1016/S0198-8859(00)00174-9.PubMedGoogle Scholar
- Dyck R, Bohm C, Klomp H: Increased frequency of HLA A2/DR4 and A2/DR8 haplotypes in young saskatchewan aboriginal people with diabetic end-stage renal disease. Am J Nephrol. 2003, 23: 178-185. 10.1159/000070747.PubMedGoogle Scholar
- Freedman BI, Spray BJ, Dunston GM, Heise ER: HLA associations in end-stage renal disease due to membranous glomerulonephritis: HLA-DR3 associations with progressive renal injury. Southeastern Organ Procurement Foundation. Am J Kidney Dis. 1994, 23: 797-802.PubMedGoogle Scholar
- Cogan MG, Medical Staff Conference: Tubulo-interstitial nephropathies--a pathophysiologic approach. West J Med. 1980, 132: 134-140.PubMed CentralPubMedGoogle Scholar
- Strutz F, Neilson EG: The role of lymphocytes in the progression of interstitial disease. Kidney Int Suppl. 1994, 45: S106-110.PubMedGoogle Scholar
- Braden GL, O'Shea MH, Mulhern JG: Tubulointerstitial diseases. Am J Kidney Dis. 2005, 46: 560-572. 10.1053/j.ajkd.2005.03.024.PubMedGoogle Scholar
- Norman JT, Fine LG: Progressive renal disease: fibroblasts, extracellular matrix, and integrins. Exp Nephrol. 1999, 7: 167-177. 10.1159/000020597.PubMedGoogle Scholar
- Okoń K, Sułowicz W, Smoleński O, Sydor A, Chruściel B, Kirker-Nowak A, Rosiek Z, Sysło K, Stachura J: Interstitial, tubular and vascular factors in progression of primary glomerulonephritis. Pol J Pathol. 2007, 58: 73-78.PubMedGoogle Scholar
- Piscator M: Early detection of tubular dysfunction. Kidney Int. 1991, 34: S15-17.Google Scholar
- Blythe WB: Natural history of hypertension in renal parenchymal disease. Am J Kidney Dis. 1985, 5: A50-56.PubMedGoogle Scholar
- Rosario RF, Wesson DE: Primary hypertension and nephropathy. Curr Opin Nephrol Hypertens. 2006, 15: 130-134. 10.1097/01.mnh.0000214771.88737.ee.PubMedGoogle Scholar
- Sugiura T, Wada A: Resistive index predicts renal prognosis in chronic kidney disease. Nephrol Dial Transplant. 2009, 24: 2780-2785. 10.1093/ndt/gfp121.PubMedGoogle Scholar
- Mujais S, Batlle DC: Functional correlates of tubulo-interstitial damage. Semin Nephrol. 1988, 8: 94-99.PubMedGoogle Scholar
- Eknoyan G, Qunibi WY, Grissom RT, Tuma SN, Ayus JC: Renal papillary necrosis: an update. Medicine (Baltimore). 1982, 61: 55-73.Google Scholar
- Kelly CJ: Cellular immunity and the tubulointerstitium. Semin Nephrol. 1999, 19: 182-187.PubMedGoogle Scholar
- Eddy AA: Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol. 1996, 7: 2495-508.PubMedGoogle Scholar
- Johnson DW, Saunders HJ, Baxter RC, Field MJ, Pollock CA: Paracrine stimulation of human renal fibroblasts by proximal tubule cells. Kidney Int. 1998, 54: 747-757. 10.1046/j.1523-1755.1998.00048.x.PubMedGoogle Scholar
- Klahr S, Morrissey JJ: The role of growth factors, cytokines, and vasoactive compounds in obstructive nephropathy. Semin Nephrol. 1998, 18: 622-632.PubMedGoogle Scholar
- Palmer BF: The renal tubule in the progression of chronic renal failure. J Investig Med. 1997, 45: 346-361.PubMedGoogle Scholar
- Wardle EN: Modulatory proteins and processes in alliance with immune cells, mediators, and extracellular proteins in renal interstitial fibrosis. Ren Fail. 1999, 21: 121-133. 10.3109/08860229909066977.PubMedGoogle Scholar
- Nony PA, Schnellmann RG: Interactions between collagen IV and collagen-binding integrins in renal cell repair after sublethal injury. Mol Pharmacol. 2001, 60: 1226-1234.PubMedGoogle Scholar
- Liu Y: Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol. 2004, 15: 1-12. 10.1097/01.ASN.0000106015.29070.E7.PubMedGoogle Scholar
- Lopez-Novoa JM, Nieto MA: Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009, 1: 303-314. 10.1002/emmm.200900043.PubMed CentralPubMedGoogle Scholar
- Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG: Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002, 110: 341-350.PubMed CentralPubMedGoogle Scholar
- Zeisberg M, Kalluri R: The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med. 2004, 82: 175-181. 10.1007/s00109-003-0517-9.PubMedGoogle Scholar
- Grande MT, López-Novoa JM: Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol. 2009, 5: 319-328. 10.1038/nrneph.2009.74.PubMedGoogle Scholar
- Zeisberg M, Duffield JS: Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol. 2010, 21: 1247-1253. 10.1681/ASN.2010060616.PubMedGoogle Scholar
- Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV: Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell. 2008, 2: 284-291. 10.1016/j.stem.2008.01.014.PubMedGoogle Scholar
- Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS: Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010, 176: 85-97. 10.2353/ajpath.2010.090517.PubMed CentralPubMedGoogle Scholar
- Becker GJ, Hewitson TD: The role of tubulointerstitial injury in chronic renal failure. Curr Opin Nephrol Hypertens. 2000, 9: 133-138. 10.1097/00041552-200003000-00006.PubMedGoogle Scholar
- Gibbs SR, Goins RA, Belvin EL, Dimari SJ, Merriam AP, Bowling-Brown S, Harris RC, Haralson MA: Characterization of the collagen phenotype of rabbit proximal tubule cells in culture. Connect Tissue Res. 1999, 40: 173-188. 10.3109/03008209909005281.PubMedGoogle Scholar
- Matsumoto Y, Ueda S, Yamagishi S, Matsuguma K, Shibata R, Fukami K, Matsuoka H, Imaizumi T, Okuda S: Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. J Am Soc Nephrol. 2007, 18: 1525-1533. 10.1681/ASN.2006070696.PubMedGoogle Scholar
- Eddy AA: Progression in chronic kidney disease. Adv Chronic Kidney Dis. 2005, 12: 353-365. 10.1053/j.ackd.2005.07.011.PubMedGoogle Scholar
- Nath KA: Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis. 1992, 20: 1-17.PubMedGoogle Scholar
- Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC: Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis. Kidney Int. 1995, 48: 753-760. 10.1038/ki.1995.347.PubMedGoogle Scholar
- Nath KA: The tubulointerstitium in progressive renal disease. Kidney Int. 1998, 54: 992-994. 10.1046/j.1523-1755.1998.00079.x.PubMedGoogle Scholar
- Wang Y, Chen J, Chen L, Tay YC, Rangan GK, Harris DC: Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol. 1997, 8: 1537-1545.PubMedGoogle Scholar
- Grandaliano G, Gesualdo L, Ranieri E, Monno R, Montinaro V, Marra F, Schena FP: Monocyte chemotactic peptide-1 expression in acute and chronic human nephritides: a pathogenetic role in interstitial monocytes recruitment. J Am Soc Nephrol. 1996, 7: 906-913.PubMedGoogle Scholar
- Tesch GH, Maifert S, Schwarting A, Rollins BJ, Kelley VR: Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice. J Exp Med. 1999, 190: 1813-1824. 10.1084/jem.190.12.1813.PubMed CentralPubMedGoogle Scholar
- Rodemann HP, Muller GA: Abnormal growth and clonal proliferation of fibroblasts derived from kidneys with interstitial fibrosis. Proc Soc Exp Biol Med. 1990, 195: 57-63.PubMedGoogle Scholar
- Rodemann HP, Muller GA: Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am J Kidney Dis. 1991, 17: 684-686.PubMedGoogle Scholar
- El Nahas AM, Bello AK: Chronic kidney disease: the global challenge. Lancet. 2005, 365: 331-340.Google Scholar
- Chevalier RL: Obstructive nephropathy: towards biomarker discovery and gene therapy. Nat Clin Pract Nephrol. 2006, 2: 157-168. 10.1038/ncpneph0098.PubMedGoogle Scholar
- Essawy M, Soylemezoglu O, Muchaneta-Kubara EC, Shortland J, Brown CB, el Nahas AM: Myofibroblasts and the progression of diabetic nephropathy. Nephrol Dial Transplant. 1997, 12: 43-50. 10.1093/ndt/12.1.43.PubMedGoogle Scholar
- Roberts IS, Burrows C, Shanks JH, Venning M, McWilliam LJ: Interstitial myofibroblasts: predictors of progression in membranous nephropathy. J Clin Pathol. 1997, 50: 123-127. 10.1136/jcp.50.2.123.PubMed CentralPubMedGoogle Scholar
- Boukhalfa G, Desmouliere A, Rondeau E, Gabbiani G, Sraer JD: Relationship between alpha-smooth muscle actin expression and fibrotic changes in human kidney. Exp Nephrol. 1996, 4: 241-247.PubMedGoogle Scholar
- Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG: Identification and characterization of a fibroblast marker: FSP1. J Cell Biol. 1995, 130: 393-405. 10.1083/jcb.130.2.393.PubMedGoogle Scholar
- Schlondorff D: The role of chemokines in the initiation and progression of renal disease. Kidney Int Suppl. 1995, 49: S44-47.PubMedGoogle Scholar
- Bohle A, Mackensen-Haen S, Wehrmann M: Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res. 1996, 19: 191-195. 10.1159/000174072.PubMedGoogle Scholar
- Mezzano SA, Aros CA, Droguett A, Burgos ME, Ardiles LG, Flores CA, Carpio D, Vío CP, Ruiz-Ortega M, Egido J: Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy. Kidney Int Suppl. 2003, 86: S39-45. 10.1046/j.1523-1755.64.s86.8.x.PubMedGoogle Scholar
- García-Sánchez O, López-Hernández FJ, Lopez-Novoa JM: An integrative view on the role of TGF-beta in the progressive tubular deletion associated with chronic kidney disease. Kidney Int. 2010, 77: 950-955.PubMedGoogle Scholar
- Eddy AA: Molecular basis of renal fibrosis. Pediatr Nephrol. 2000, 15: 290-301. 10.1007/s004670000461.PubMedGoogle Scholar
- Liu Y: Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 2006, 69: 213-217. 10.1038/sj.ki.5000054.PubMedGoogle Scholar
- Singer AJ, Clark RA: Cutaneous wound healing. N Engl J Med. 1999, 341: 738-746. 10.1056/NEJM199909023411006.PubMedGoogle Scholar
- Eddy AA: Role of cellular infiltrates in response to proteinuria. Am J Kidney Dis. 2001, 37: S25-29. 10.1053/ajkd.2001.20735.PubMedGoogle Scholar
- Nishida M, Fujinaka H, Matsusaka T, Price J, Kon V, Fogo AB, Davidson JM, Linton MF, Fazio S, Homma T, Yoshida H, Ichikawa I: Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis. J Clin Invest. 2002, 110: 1859-1868.PubMed CentralPubMedGoogle Scholar
- Van Goor H, Ding G, Kees-Folts D, Grond J, Schreiner GF, Diamond JR: Macrophages and renal disease. Lab Invest. 1994, 71: 456-464.PubMedGoogle Scholar
- Vleming LJ, Bruijn JA, van Es LA: The pathogenesis of progressive renal failure. Neth J Med. 1999, 54: 114-128. 10.1016/S0300-2977(98)00151-X.PubMedGoogle Scholar
- Gharaee-Kermani M, Wiggins R, Wolber F, Goyal M, Phan SH: Fibronectin is the major fibroblast chemoattractant in rabbit anti-glomerular basement membrane disease. Am J Pathol. 1996, 148: 961-967.PubMed CentralPubMedGoogle Scholar
- Eddy AA: Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions. J Am Soc Nephrol. 1994, 5: 1273-1277.PubMedGoogle Scholar
- Van Vliet A, Baelde HJ, Vleming LJ, de Heer E, Bruijn JA: Distribution of fibronectin isoforms in human renal disease. J Pathol. 2001, 193: 256-262. 10.1002/1096-9896(2000)9999:9999<::AID-PATH783>3.0.CO;2-P.PubMedGoogle Scholar
- Wells AF, Larsson E, Tengblad A, Fellström B, Tufveson G, Klareskog L, Laurent TC: The localization of hyaluronan in normal and rejected human kidneys. Transplantation. 1990, 50: 240-243. 10.1097/00007890-199008000-00014.PubMedGoogle Scholar
- Beck-Schimmer B, Oertli B, Pasch T, Wuthrich RP: Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells. J Am Soc Nephrol. 1998, 9: 2283-2290.PubMedGoogle Scholar
- Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N: Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell. 1998, 93: 1159-1170. 10.1016/S0092-8674(00)81460-9.PubMedGoogle Scholar
- Hugo C, Shankland SJ, Pichler RH, Couser WG, Johnson RJ: Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat. Kidney Int. 1998, 53: 302-311. 10.1046/j.1523-1755.1998.00774.x.PubMedGoogle Scholar
- Diamond JR, Levinson M, Kreisberg R, Ricardo SD: Increased expression of decorin in experimental hydronephrosis. Kidney Int. 1997, 51: 1133-1139. 10.1038/ki.1997.156.PubMedGoogle Scholar
- Schaefer L, Hausser H, Altenburger M, Ugorcakova J, August C, Fisher LW, Schaefer RM, Kresse H: Decorin, biglycan and their endocytosis receptor in rat renal cortex. Kidney Int. 1998, 54: 1529-1541. 10.1046/j.1523-1755.1998.00149.x.PubMedGoogle Scholar
- Gonzalez-Avila G, Vadillo-Ortega F, Perez-Tamayo R: Experimental diffuse interstitial renal fibrosis. A biochemical approach. Lab Invest. 1988, 59: 245-252.PubMedGoogle Scholar
- Border WA, Noble NA: Transforming growth factor beta in tissue fibrosis. N Engl J Med. 1994, 331: 1286-1292. 10.1056/NEJM199411103311907.PubMedGoogle Scholar
- Cheng J, Grande JP: Transforming growth factor-beta signal transduction and progressive renal disease. Exp Biol Med (Maywood). 2002, 227: 943-956.Google Scholar
- Roberts AB, McCune BK, Sporn MB: TGF-beta: regulation of extracellular matrix. Kidney Int. 1992, 41: 557-559. 10.1038/ki.1992.81.PubMedGoogle Scholar
- Hultström M, Leh S, Skogstrand T, Iversen BM: Upregulation of tissue inhibitor of metalloproteases-1 (TIMP-1) and procollagen-N-peptidase in hypertension-induced renal damage. Nephrol Dial Transplant. 2008, 23: 896-903.PubMedGoogle Scholar
- Kim H, Oda T, Lopez-Guisa J, Wing D, Edwards DR, Soloway PD, Eddy AA: TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol. 2000, 12: 736-748.Google Scholar
- Klahr S: Progression of chronic renal disease. Heart Dis. 2001, 3: 205-209. 10.1097/00132580-200105000-00013.PubMedGoogle Scholar
- García-Sánchez O, López-Hernández FJ, López-Novoa JM: An integrative view on the role of TGF-beta in the progressive tubular deletion associated with chronic kidney disease. Kidney Int. 2010, 77: 950-955.PubMedGoogle Scholar
- Nangaku M: Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006, 17: 17-25. 10.1681/ASN.2005070757.PubMedGoogle Scholar
- Ortiz A, Lorz C, Egido J: The Fas ligand/Fas system in renal injury. Nephrol Dial Transplant. 1999, 14: 1831-1834. 10.1093/ndt/14.8.1831.PubMedGoogle Scholar
- Kelly DJ, Stein-Oakley A, Zhang Y, Wassef L, Maguire J, Koji T, Thomson N, Wilkinson-Berka JL, Gilbert RE: Fas-induced apoptosis is a feature of progressive diabetic nephropathy in transgenic (mRen-2)27 rats: attenuation with renin-angiotensin blockade. Nephrology. 2004, 9: 7-13. 10.1111/j.1440-1797.2003.00227.x.PubMedGoogle Scholar
- Lorz C, Ortiz A, Justo P, González-Cuadrado S, Duque N, Gómez-Guerrero C, Egido J: Proapoptotic Fas ligand is expressed by normal kidney tubular epithelium and injured glomeruli. J Am Soc Nephrol. 2000, 11: 1266-1277.PubMedGoogle Scholar
- Khan S, Koepke K, Jarad G, Schlessman K, Cleveland RP, Wang B, Konieczkowski M, Schelling JR: Apoptosis and JNK activation are differentially regulated by Fas expression level in renal tubular epithelial cells. Kidney Int. 2001, 60: 65-76. 10.1046/j.1523-1755.2001.00771.x.PubMedGoogle Scholar
- Jarad G, Wang B, Khan S, DeVore J, Miao H, Wu K, Nishimura SL, Wible BA, Konieczkowski M, Sedor JR, Schelling JR: Fas activation induces renal tubular epithelial cell beta 8 integrin expression and function in the absence of apoptosis. J Biol Chem. 2002, 277: 47826-47833. 10.1074/jbc.M204901200.PubMedGoogle Scholar
- Santiago B, Galindo M, Palao G, Pablos JL: Intracellular regulation of Fas-induced apoptosis in human fibroblasts by extracellular factors and cycloheximide. J Immunol. 2004, 172: 560-566.PubMedGoogle Scholar
- Miyajima A, Chen J, Lawrence C, Ledbetter S, Soslow RA, Stern J, Jha S, Pigato J, Lemer ML, Poppas DP, Vaughan ED, Felsen D: Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int. 2000, 58: 2301-2313. 10.1046/j.1523-1755.2000.00414.x.PubMedGoogle Scholar
- Kelly DJ, Cox AJ, Tolcos M, Cooper ME, Wilkinson-Berka JL, Gilbert RE: Attenuation of tubular apoptosis by blockade of the renin-angiotensin system in diabetic Ren-2 rats. Kidney Int. 2002, 61: 31-39. 10.1046/j.1523-1755.2002.00088.x.PubMedGoogle Scholar
- Bhaskaran M, Reddy K, Radhakrishanan N, Franki N, Ding G, Singhal PC: Angiotensin II induces apoptosis in renal proximal tubular cells. Am J Physiol Ren Physiol. 2003, 284: F955-965.Google Scholar
- Ortiz-Arduan A, Danoff TM, Kalluri R, González-Cuadrado S, Karp SL, Elkon K, Egido J, Neilson EG: Regulation of Fas and Fas ligand expression in cultured murine renal cells and in the kidney during endotoxemia. Am J Physiol. 1996, 271: F1193-1201.PubMedGoogle Scholar
- Schelling JR, Nkemere N, Kopp JB, Cleveland RP: Fas-dependent fratricidal apoptosis is a mechanism of tubular epithelial cell deletion in chronic renal failure. Lab Invest. 1998, 78: 813-824.PubMedGoogle Scholar
- Khan S, Cleveland RP, Koch CJ, Schelling JR: Hypoxia induces renal tubular epithelial cell apoptosis in chronic renal disease. Lab Invest. 1999, 79: 1089-1099.PubMedGoogle Scholar
- Koesters R, Kaissling B, Lehir M, Picard N, Theilig F, Gebhardt R, Glick AB, Hähnel B, Hosser H, Gröne HJ, Kriz W: Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am J Pathol. 2010, 177: 632-643. 10.2353/ajpath.2010.091012.PubMed CentralPubMedGoogle Scholar
- Sanz AB, Santamaria B, Ruiz Ortega M, Egido J, Ortiz A: Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol. 2008, 19: 1634-1642. 10.1681/ASN.2007121336.PubMedGoogle Scholar
- Ichikawi I, Harris RC: Angiotensin actions in the kidney: renewed insight into the old hormone. Kidney Int. 1991, 40: 583-596. 10.1038/ki.1991.249.PubMedGoogle Scholar
- Wang CZ, Hsu YM, Tang MJ: Function of discoidin domain receptor I in HGF-induced branching tubulogenesis of MDCK cells in collagen gel. J Cell Physiol. 2005, 203: 295-304. 10.1002/jcp.20227.PubMedGoogle Scholar
- Hughes J: Life and death in the kidney: prospects for future therapy. Nephrol Dial Transplant. 2001, 16: 879-882. 10.1093/ndt/16.5.879.PubMedGoogle Scholar
- De Broe ME: Apoptosis in acute renal failure. Nephrol Dial Transplant. 2001, 16 (Suppl 6): 23-26.PubMedGoogle Scholar
- Nilakantan V, Maenpaa C, Jia G, Roman RJ, Park F: 20-HETE-mediated cytotoxicity and apoptosis in ischemic kidney epithelial cells. Am J Physiol Renal Physiol. 2008, 294: F562-570. 10.1152/ajprenal.00387.2007.PubMed CentralPubMedGoogle Scholar
- Orphanides C, Fine LG, Norman JT: Hypoxia stimulates proximal tubular cell matrix production via a TGF-beta1-independent mechanism. Kidney Int. 1997, 52: 637-647. 10.1038/ki.1997.377.PubMedGoogle Scholar
- Haase VH: Pathophysiological Consequences of HIF Activation: HIF as a modulator of fibrosis. Ann N Y Acad Sci. 2009, 1177: 57-65. 10.1111/j.1749-6632.2009.05030.x.PubMed CentralPubMedGoogle Scholar
- López-Novoa JM, Nieto MA: Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009, 1: 303-314.PubMed CentralPubMedGoogle Scholar
- Serón D, Alexopoulos E, Raftery MJ, Hartley B, Cameron JS: Number of interstitial capillary cross-sections assessed by monoclonal antibodies: relation to interstitial damage. Nephrol Dial Transplant. 1990, 5: 889-893.PubMedGoogle Scholar
- Couser WG: Pathogenesis of glomerular damage in glomerulonephritis. Nephrol Dial Transplant. 1998, 13: 10-15. 10.1093/ndt/13.suppl_1.10.PubMedGoogle Scholar
- Isaka Y, Akagi Y, Ando Y, Tsujie M, Imai E: Cytokines and glomerulosclerosis. Nephrol Dial Transplant. 1999, 14: 30-32. 10.1093/ndt/14.suppl_1.30.PubMedGoogle Scholar
- Nangaku M, Couser WG: Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol. 2005, 9: 183-191. 10.1007/s10157-005-0357-8.PubMedGoogle Scholar
- Couser WG: Complement inhibitors and glomerulonephritis: are we there yet?. J Am Soc Nephrol. 2003, 14: 815-818. 10.1097/01.ASN.0000057502.76239.7D.PubMedGoogle Scholar
- Cunard R, Jelly CJ: Immune-mediated renal disease. J Allergy Clin Immunol. 2003, 111: S637-644. 10.1067/mai.2003.126.PubMedGoogle Scholar
- Shimizu A, Masuda Y, Kitamura H, Ishizaki M, Sugisaki Y, Yamanaka N: Recovery of damaged glomerular capillary network with endothelial cell apoptosis in experimental proliferative glomerulonephritis. Nephron. 1998, 79: 206-214. 10.1159/000045026.PubMedGoogle Scholar
- U.S. Renal Data System, USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2005. http://www.usrds.org/atlas.htm
- López-Hernández FJ, López-Novoa JM: The lord of the ring: Mandatory role of the kidney in drug therapy of hypertension. Pharmacol Ther. 2006, 111: 53-80.PubMedGoogle Scholar
- López-Novoa JM, Martínez-Salgado C, Rodríguez-Peña AB, López Hernández FJ: Common pathophysiological mechanisms of chronic kidney disease: Therapeutic perspectives. Pharmacol Ther. 2010, 128: 61-81.PubMedGoogle Scholar
- Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, Ferrario F, Fogo AB, Haas M, de Heer E, Joh K, Noël LH, Radhakrishnan J, Seshan SV, Bajema IM, Bruijn JA, Renal Pathology Society: Pathologic Classification of Diabetic Nephropathy. J Am Soc Nephrol. 2010, 21: 556-563. 10.1681/ASN.2010010010.PubMedGoogle Scholar
- Wesson LG: Physical factors and glomerulosclerosis. Cause or coincidence?. Nephron. 1998, 78: 125-130. 10.1159/000044899.PubMedGoogle Scholar
- Wiggins RC: The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int. 2007, 71: 1205-1214. 10.1038/sj.ki.5002222.PubMedGoogle Scholar
- Ziyadeh FN, Wolf G: Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev. 2008, 4: 39-45. 10.2174/157339908783502370.PubMedGoogle Scholar
- Moreno JA, Sanchez-Niño MD, Sanz AB, Lassila M, Holthofer H, Blanco-Colio LM, Egido J, Ruiz-Ortega M, Ortiz A: A slit in podocyte death. Curr Med Chem. 2008, 15: 1645-1654. 10.2174/092986708784911542.PubMedGoogle Scholar
- Kang YS, Li Y, Dai C, Kiss LP, Wu C, Liu Y: Inhibition of integrin-linked kinase blocks podocyte epithelial-mesenchymal transition and ameliorates proteinuria. Kidney Int. 2010, 78: 363-373. 10.1038/ki.2010.137.PubMed CentralPubMedGoogle Scholar
- Kriz W, LeHir M: Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int. 2005, 67: 404-419. 10.1111/j.1523-1755.2005.67097.x.PubMedGoogle Scholar
- Harris RC, Akai Y, Yasuda T, Homma T: The role of physical forces in alterations of mesangial cell function. Kidney Int Suppl. 1994, 45: S17-21.PubMedGoogle Scholar
- Funabiki K, Horikoshi S, Tomino Y, Nagai Y, Koide H: Immunohistochemical analysis of extracellular components in the glomerular sclerosis of patients with glomerulonephritis. Clin Nephrol. 1990, 34: 239-246.PubMedGoogle Scholar
- Makino H, Kashihara N, Sugiyama H, Sekikawa T, Ota Z: Role of apoptosis in the progression of glomerulosclerosis. Contrib Nephrol. 1996, 118: 41-47.PubMedGoogle Scholar
- Kurogi Y: Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease. Med Res Rev. 2003, 23: 15-31. 10.1002/med.10028.PubMedGoogle Scholar
- Morel-Maroger Striker L, Killen PD, Chi E, Striker GE: The composition of glomerulosclerosis. I. Studies in focal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Lab Invest. 1984, 51: 181-192.PubMedGoogle Scholar
- Floege J, Johnson RJ, Couser WG: Mesangial cells in the pathogenesis of progressive glomerular disease in animal models. Clin Investig. 1992, 70: 857-864. 10.1007/BF00180756.PubMedGoogle Scholar
- Massy ZA, Guijarro C, O'Donnell MP, Kim Y, Kashtan CE, Egido J, Kasiske BL, Keane WF: The central role of nuclear factor-kappa B in mesangial cell activation. Kidney Int. 1999, 71: S76-79. 10.1046/j.1523-1755.1999.07119.x.Google Scholar
- Johnson RJ, Alpers CE, Yoshimura A, Lombardi D, Pritzl P, Floege J, Schwartz SM: Renal injury from angiotensin II-mediated hypertension. Hypertension. 1992, 19: 464-474.PubMedGoogle Scholar
- Ardaillou R, Chansel D, Chatziantoniou C, Dussaule JC: Mesangial AT1 receptors: expression, signaling, and regulation. J Am Soc Nephrol. 1999, 10: S40-46.PubMedGoogle Scholar
- Kagami S, Kondo S, Löster K, Reutter W, Kuhara T, Yasutomo K, Kuroda Y: Alpha1beta1 integrin-mediated collagen matrix remodeling by rat mesangial cells is differentially regulated by transforming growth factor-beta and platelet-derived growth factor-BB. J Am Soc Nephrol. 1999, 10: 779-789.PubMedGoogle Scholar
- Haberstroh U, Zahner G, Disser M, Thaiss F, Wolf G, Stahl RA: TGF-beta stimulates rat mesangial cell proliferation in culture: role of PDGF beta-receptor expression. Am J Physiol. 1993, 264: F199-205.PubMedGoogle Scholar
- Bessho K, Mizuno S, Matsumoto K, Nakamura T: Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis. Am J Physiol Renal Physiol. 2003, 284: F1171-180.PubMedGoogle Scholar
- Gomez-Garre D, Ruiz-Ortega M, Ortego M, Largo R, López-Armada MJ, Plaza JJ, González E, Egido J: Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension. 1996, 27: 885-892.PubMedGoogle Scholar
- Hahn S, Krieg RJ, Hisano S, Chan W, Kuemmerle NB, Saborio P, Chan JC: Vitamin E suppresses oxidative stress and glomerulosclerosis in rat remnant kidney. Pediatr Nephrol. 1999, 13: 195-198. 10.1007/s004670050591.PubMedGoogle Scholar
- Jaimes EA, Galceran JM, Raij L: Angiotensin II induces superoxide anion production by mesangial cells. Kidney Int. 1998, 54: 775-784. 10.1046/j.1523-1755.1998.00068.x.PubMedGoogle Scholar
- Couser WG: Pathogenesis of glomerulonephritis. Kidney Int. 1993, 42: S19-26.Google Scholar
- Grande MT, Perez-Barriocanal F, Lopez-Novoa JM: Role of inflammation in túbulo-interstitial damage associated to obstructive nephropathy. J Inflamm (Lond). 2010, 7: 19-10.1186/1476-9255-7-19.Google Scholar
- Johnson RJ, Iida H, Alpers CE, Majesky MW, Schwartz SM, Pritzi P, Gordon K, Gown AM: Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation. J Clin Invest. 1991, 87: 847-858. 10.1172/JCI115089.PubMed CentralPubMedGoogle Scholar
- Alpers CE, Hudkins KL, Gown AM, Johnson RJ: Enhanced expression of "muscle-specific" actin in glomerulonephritis. Kidney Int. 1992, 41: 1134-1142. 10.1038/ki.1992.173.PubMedGoogle Scholar
- Stokes MB, Holler S, Cui Y, Hudkins KL, Eitner F, Fogo A, Alpers CE: Expression of decorin, biglycan, and collagen type I in human renal fibrosing disease. Kidney Int. 2000, 57: 487-498. 10.1046/j.1523-1755.2000.00868.x.PubMedGoogle Scholar
- Couser WG, Johnson RJ: Mechanisms of progressive renal disease in glomerulonephritis. Am J Kidney Dis. 1994, 23: 193-198.PubMedGoogle Scholar
- Justo P, Sanz AB, Sanchez-Niño MD, Winkles JA, Lorz C, Egido J, Ortiz A: Cytokine cooperation in renal tubular cell injury: the role of TWEAK. Kidney Int. 2006, 70: 1750-1758. 10.1038/sj.ki.5001866.PubMedGoogle Scholar
- Sanchez-Niño MD, Benito-Martin A, Gonçalves S, Sanz AB, Ucero AC, Izquierdo MC, Ramos AM, Berzal S, Selgas R, Ruiz-Ortega M, Egido J, Ortiz A: TNF superfamily: a growing saga of kidney injury modulators. Mediators Inflamm.Google Scholar
- Strutz F, Neilson EG: New insights into mechanisms of fibrosis in immune renal injury. Springer Semin Immunopathol. 2003, 24: 459-476. 10.1007/s00281-003-0123-5.PubMedGoogle Scholar
- Border WA, Noble NA: TGF-beta in kidney fibrosis: a target for gene therapy. Kidney Int. 1997, 51: 1388-1396. 10.1038/ki.1997.190.PubMedGoogle Scholar
- Tamaki K, Okuda S: Role of TGF-beta in the progression of renal fibrosis. Contrib Nephrol. 2003, 139: 44-65. full_text.PubMedGoogle Scholar
- Chiarugi A: ''Simple but not simpler'': toward a unified picture of energy requirements in cell death. FASEB J. 2005, 19: 1783-1788. 10.1096/fj.05-4200rev.PubMedGoogle Scholar
- Rusterholz C, Gupta AK, Huppertz B, Holzgreve W, Hahn S: Soluble factors released by placental villous tissue: Interleukin-1 is a potential mediator of endothelial dysfunction. Am J Obstet Gynecol. 2005, 192: 618-624. 10.1016/j.ajog.2004.08.029.PubMedGoogle Scholar
- Gao X, Zhang H, Belmadani S, Wu J, Xu X, Elford H, Potter BJ, Zhang C: Role of TNF-alpha-induced reactive oxygen species in endothelial dysfunction during reperfusion injury. Am J Physiol Heart Circ Physiol. 2008, 295: H2242-2249. 10.1152/ajpheart.00587.2008.PubMed CentralPubMedGoogle Scholar
- Zhang C, Wu J, Xu X, Potter BJ, Gao X: Direct relationship between levels of TNF-alpha expression and endothelial dysfunction in reperfusion injury. Basic Res Cardiol. 2010, 105: 453-464. 10.1007/s00395-010-0083-6.PubMed CentralPubMedGoogle Scholar
- Camussi G, Turello E, Tetta C, Bussolino F, Baglioni C: Tumor necrosis factor induces contraction of mesangial cells and alters their cytoskeletons. Kidney Int. 1990, 38: 795-802. 10.1038/ki.1990.273.PubMedGoogle Scholar
- López-Farré A, Gómez-Garre D, Bernabeu F, Montañés I, Millás I, López-Novoa JM: Renal effects and mesangial cell contraction induced by endothelin are mediated by PAF. Kidney Int. 1991, 39: 624-630.PubMedGoogle Scholar
- Bussolati B, Mariano F, Biancone L, Foà R, David S, Cambi V, Camussi G: Interleukin-12 is synthesized by mesangial cells and stimulates platelet-activating factor synthesis, cytoskeletal reorganization, and cell shape change. Am J Pathol. 1999, 154: 623-632. 10.1016/S0002-9440(10)65307-2.PubMed CentralPubMedGoogle Scholar
- López-Novoa JM: Potential role of platelet activating factor in acute renal failure. Kidney Int. 1999, 55: 1672-1682.PubMedGoogle Scholar
- Molitoris BA, Sutton TA: Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int. 2004, 66: 496-499. 10.1111/j.1523-1755.2004.761_5.x.PubMedGoogle Scholar
- Bonventre JV: Pathophysiology of AKI: injury and normal and abnormal repair. Contrib Nephrol. 2010, 165: 9-17. full_text.PubMedGoogle Scholar
- Rodriguez-Barbero A, L'Azou B, Cambar J, López-Novoa JM: Potential use of isolated glomeruli and cultured mesangial cells as in vitro models to assess nephrotoxicity. Cell Biol Toxicol. 2000, 16: 145-153. 10.1023/A:1007683320660.PubMedGoogle Scholar
- Wolf G, Ziyadeh FN: Cellular and molecular mechanisms of proteinuria in diabetic nephropathy. Nephron Physiol. 2007, 106: p26-p31. 10.1159/000101797.PubMedGoogle Scholar
- Ziyadeh FN, Wolf G: Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev. 2008, 4: 39-45. 10.2174/157339908783502370.PubMedGoogle Scholar
- Smeets B, Dijkman H, Wetzels J, Steenbergen EJ: Lessons from studies on focal segmental glomerulosclerosis: an important role for parietal epithelial cells?. J Pathol. 2006, 210: 263-272. 10.1002/path.2051.PubMedGoogle Scholar
- Asano T, Niimura F, Pastan I, Fogo AB, Ichikawa I, Matsusaka T: Permanent genetic tagging of podocytes: fate of injured podocytes in a mouse model of glomerular sclerosis. J Am Soc Nephrol. 2005, 16: 2257-2262. 10.1681/ASN.2004121134.PubMedGoogle Scholar
- Pätäri-Sampo A, Ihalmo P, Holthöfer H: Molecular basis of the glomerular filtration: nephrin and the emerging protein complex at the podocyte slit diaphragm. Ann Med. 2006, 38: 483-492.PubMedGoogle Scholar
- Barisoni L, Mundel P: Podocyte biology and the emerging understanding of podocyte diseases. Am J Nephrol. 2003, 23: 353-360. 10.1159/000072917.PubMedGoogle Scholar
- Remuzzi G, Bertani T: Pathophysiology of progressive nephropathies. N Engl J Med. 1998, 339: 1448-1456. 10.1056/NEJM199811123392007.PubMedGoogle Scholar
- Morioka Y, Koike H, Ikezumi Y, Ito Y, Oyanagi A, Gejyo F, Shimizu F, Kawachi H: Podocyte injuries exacerbate mesangial proliferative glomerulonephritis. Kidney Int. 2001, 60: 2192-2204. 10.1046/j.1523-1755.2001.00047.x.PubMedGoogle Scholar
- Sawai K, Mori K, Mukoyama M, Sugawara A, Suganami T, Koshikawa M, Yahata K, Makino H, Nagae T, Fujinaga Y, Yokoi H, Yoshioka T, Yoshimoto A, Tanaka I, Nakao K: Angiogenic protein Cyr61 is expressed by podocytes in anti-Thy-1 glomerulonephritis. J Am Soc Nephrol. 2003, 14: 1154-1163. 10.1097/01.ASN.0000060576.61218.3D.PubMedGoogle Scholar
- Chen S, Kasama Y, Lee JS, Jim B, Marin M, Ziyadeh FN: Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes. Diabetes. 2004, 53: 2939-2949. 10.2337/diabetes.53.11.2939.PubMedGoogle Scholar
- Kang YS, Park YG, Kim BK, Han SY, Jee YH, Han KH, Lee MH, Song HK, Cha DR, Kang SW, Han DS: Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes. J Mol Endocrinol. 2006, 36: 377-388. 10.1677/jme.1.02033.PubMedGoogle Scholar
- Wang L, Kwak JH, Kim SI, He Y, Choi ME: Transforming growth factor-beta1 stimulates vascular endothelial growth factor 164 via mitogen-activated protein kinase kinase 3-p38alpha and p38delta mitogen-activated protein kinase-dependent pathway in murine mesangial cells. J Biol Chem. 2004, 279: 33213-33219. 10.1074/jbc.M403758200.PubMedGoogle Scholar
- Kriz W, Gretz N, Lemley KV: Progression of glomerular diseases: Is the podocyte the culprit?. Kidney Int. 1998, 54: 687-697. 10.1046/j.1523-1755.1998.00044.x.PubMedGoogle Scholar
- Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW: Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 1997, 99: 342-348. 10.1172/JCI119163.PubMed CentralPubMedGoogle Scholar
- Lemley KV, Lafayette RA, Safai M, Derby G, Blouch K, Squarer A, Myers BD: Podocytopenia and disease severity in IgA nephropathy. Kidney Int. 2002, 61: 1475-1485. 10.1046/j.1523-1755.2002.00269.x.PubMedGoogle Scholar
- U.S. Renal Data System, USRDS 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2002.Google Scholar
- Olin JW: Atherosclerotic renal artery disease. Cardiol Clin. 2002, 20: 547-562. 10.1016/S0733-8651(02)00091-7.PubMedGoogle Scholar
- De Mast Q, Beutler JJ: The prevalence of atherosclerotic renal artery stenosis in risk groups: a systematic literature review. J Hypertens. 2009, 27: 1333-1340. 10.1097/HJH.0b013e328329bbf4.PubMedGoogle Scholar
- Rihal CS, Textor SC, Breen JF, McKusick MA, Grill DE, Hallett JW, Holmes DR: Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography. Mayo Clin Proc. 2002, 77: 309-316. 10.4065/77.4.309.PubMedGoogle Scholar
- Garovic VD, Textor SC: Renovascular hypertension and ischemic nephropathy. Circulation. 2005, 112: 1362-1374. 10.1161/CIRCULATIONAHA.104.492348.PubMedGoogle Scholar
- Textor SC: Ischemic nephropathy: where are we now?. J Am Soc Nephrol. 2004, 15: 1974-1982. 10.1097/01.ASN.0000133699.97353.24.PubMedGoogle Scholar
- Chade AR, Rodriguez-Porcel M, Grande JP, Zhu X, Sica V, Napoli C, Sawamura T, Textor SC, Lerman A, Lerman LO: Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis. Arterioscler Thromb Vasc Biol. 2003, 23: 1295-1301. 10.1161/01.ATV.0000077477.40824.52.PubMedGoogle Scholar
- Chade AR, Lerman A, Lerman LO: Kidney in early atherosclerosis. Hypertension. 2005, 45: 1042-1049. 10.1161/01.HYP.0000167121.14254.a0.PubMedGoogle Scholar
- Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H: Role of oxidative stress in atherosclerosis. Am J Cardiol. 2003, 91: 7-11A. 10.1016/S0002-9149(02)03144-2.Google Scholar
- Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG: Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996, 97: 1916-1923. 10.1172/JCI118623.PubMed CentralPubMedGoogle Scholar
- Reckelhoff JF, Romero JC: Role of oxidative stress in angiotensin-induced hypertension. Am J Physiol Regul Integr Comp Physiol. 2003, 284: R893-912.PubMedGoogle Scholar
- Chade AR, Krier JD, Rodriguez-Porcel M, Breen JF, McKusick MA, Lerman A, Lerman LO: Comparison of acute and chronic antioxidant interventions in experimental renovascular disease. Am J Physiol Renal Physiol. 2004, 286: F1079-1086. 10.1152/ajprenal.00385.2003.PubMedGoogle Scholar
- Oliveira-Sales EB, Dugaich AP, Carillo BA, Abreu NP, Boim MA, Martins PJ, D'Almeida V, Dolnikoff MS, Bergamaschi CT, Campos RR: Oxidative stress contributes to renovascular hypertension. Am J Hypertens. 2008, 21: 98-104. 10.1038/ajh.2007.12.PubMedGoogle Scholar
- Schnackenberg CG: Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol Regul Integr Comp Physiol. 2002, 282: R335-342.PubMedGoogle Scholar
- Textor SC, Novick AC, Tarazi RC, Klimas V, Vidt DG, Pohl M: Critical perfusion pressure for renal function in patients with bilateral atherosclerotic renal vascular disease. Ann Intern Med. 1985, 102: 308-314.PubMedGoogle Scholar
- Epstein FH: Oxygen and renal metabolism. Kidney Int. 1997, 51: 381-385. 10.1038/ki.1997.50.PubMedGoogle Scholar
- Spence JD: Treatment options for renovascular hypertension. Expert Opin Pharmacother. 2002, 3: 411-416. 10.1517/146565220.127.116.111.PubMedGoogle Scholar
- Safian RD, Textor SC: Renal-artery stenosis. N Engl J Med. 2001, 344: 431-442. 10.1056/NEJM200102083440607.PubMedGoogle Scholar
- Iliescu R, Fernandez SR, Kelsen S, Maric C, Chade AR: Role of renal microcirculation in experimental renovascular disease. Nephrol Dial Transplant. 2010, 25: 1079-1087. 10.1093/ndt/gfp605.PubMed CentralPubMedGoogle Scholar
- Haase VH: Pathophysiological Consequences of HIF Activation: HIF as a modulator of fibrosis. Ann N Y Acad Sci. 2009, 1177: 57-65. 10.1111/j.1749-6632.2009.05030.x.PubMed CentralPubMedGoogle Scholar
- Moran K, Mulhall J, Kelly D, Sheehan S, Dowsett J, Dervan P, Fitzpatrick JM: Morphological changes and alterations in regional intrarenal blood flow induced by graded renal ischemia. J Urol. 1992, 148: 463-466.PubMedGoogle Scholar
- Jeong JI, Lee YW, Kim YK: Chemical hypoxia-induced cell death in human glioma cells: role of reactive oxygen species, ATP depletion, mitochondrial damage and Ca2+. Neurochem Res. 2003, 28: 1201-1211. 10.1023/A:1024280429036.PubMedGoogle Scholar
- Seppet E, Gruno M, Peetsalu A, Gizatullina Z, Nguyen HP, Vielhaber S, Wussling MH, Trumbeckaite S, Arandarcikaite O, Jerzembeck D, Sonnabend M, Jegorov K, Zierz S, Striggow F, Gellerich FN: Mitochondria and energetic depression in cell pathophysiology. Int J Mol Sci. 2009, 10: 2252-2303. 10.3390/ijms10052252.PubMed CentralPubMedGoogle Scholar
- Sato T, Oku H, Tsuruma K, Katsumura K, Shimazawa M, Hara H, Sugiyama T, Ikeda T: Effect of hypoxia on susceptibility of RGC-5 cells to nitric oxide. Invest Ophthalmol Vis Sci. 2010, 51: 2575-2486. 10.1167/iovs.09-4303.PubMedGoogle Scholar
- Kiang JG, Tsen KT: Biology of hypoxia. Chin J Physiol. 2006, 49: 223-233.PubMedGoogle Scholar
- Voiculescu A, Grabensee B, Jung G, Mödder U, Sandmann W: Renovascular disease: a review of diagnostic and therapeutic procedures. Minerva Urol Nefrol. 2006, 58: 127-149.PubMedGoogle Scholar
- Chade AR, Rodriguez-Porcel M, Grande JP, Zhu X, Sica V, Napoli C, Sawamura T, Textor SC, Lerman A, Lerman LO: Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis. Arterioscler Thromb Vasc Biol. 2003, 23: 1295-1230. 10.1161/01.ATV.0000077477.40824.52.PubMedGoogle Scholar
- Gallego B, Arevalo MA, Flores O, López-Novoa JM, Pérez-Barriocanal F: Renal fibrosis in diabetic and aortic-constricted hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2001, 280: R1823-1829.PubMedGoogle Scholar
- Gallego B, Arevalo , Flores O, López-Novoa JM, Pérez-Barriocanal F: Effect of chronic and progressive aortic constriction on renal function and structure in rats. Can J Physiol Pharmacol. 2001, 79: 601-607. 10.1139/cjpp-79-7-601.PubMedGoogle Scholar
- Textor SC: Pathophysiology of renovascular hypertension. Urol Clin North Am. 1984, 11: 373-381.PubMedGoogle Scholar
- Navar LG, Von Thun AM, Zou L, el-Dahr SS, Mitchell KD: Enhancement of intrarenal angiotensin II levels in 2 kidney 1 clip and angiotensin II induced hypertension. Blood Press Suppl. 1995, 2: 88-92.PubMedGoogle Scholar
- Zimmerman MC, Lazartigues E, Sharma RV, Davisson RL: Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res. 2004, 95: 210-216. 10.1161/01.RES.0000135483.12297.e4.PubMedGoogle Scholar
- Wolf G, Schneider A, Wenzel U, Helmchen U, Stahl RA: Regulation of glomerular TGF-beta expression in the contralateral kidney of two-kidney, one-clip hypertensive rats. J Am Soc Nephrol. 1998, 9: 763-772.PubMedGoogle Scholar
- Bohle A, Muller GA, Wehrmann M, Mackensen-Haen S, Xiao JC: Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies, and chronic interstitial nephritides. Kidney Int Suppl. 1996, 54: S2-9.PubMedGoogle Scholar
- Komlosi P, Bell PD, Zhang ZR: Tubuloglomerular feedback mechanisms in nephron segments beyond the macula densa. Curr Opin Nephrol Hypertens. 2009, 18: 57-62. 10.1097/MNH.0b013e32831daf54.PubMedGoogle Scholar
- Kriz W, Hosser H, Hahnel B, Gretz N, Provoost AP: From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies. Nephrol Dial Transplant. 1998, 13: 2781-2798. 10.1093/ndt/13.11.2781.PubMedGoogle Scholar
- Abbate M, Zoja C, Remuzzi G: How does proteinuria cause progressive renal damage?. J Am Soc Nephrol. 2006, 17: 2974-2984. 10.1681/ASN.2006040377.PubMedGoogle Scholar
- Baines RJ, Brunskill NJ: Tubular toxicity of proteinuria. Nat Rev Nephrol.Google Scholar
- Buelli S, Abbate M, Morigi M, Moioli D, Zanchi C, Noris M, Zoja C, Pusey CD, Zipfel PF, Remuzzi G: Protein load impairs factor H binding promoting complement-dependent dysfunction of proximal tubular cells. Kidney Int. 2009, 75: 1050-1059. 10.1038/ki.2009.8.PubMedGoogle Scholar
- Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E, Noris M, Buelli S, Zoja C, Corna D, Mele C, Fanelli R, Remuzzi G, Benigni A: Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am Soc Nephrol. 2009, 20: 123-130. 10.1681/ASN.2007111233.PubMed CentralPubMedGoogle Scholar
- Lapsley M, Flynn FV, Sansom PA: Beta 2-glycoprotein-1 (apolipoprotein H) excretion and renal tubular malfunction in diabetic patients without clinical proteinuria. J Clin Pathol. 1993, 46: 465-469. 10.1136/jcp.46.5.465.PubMed CentralPubMedGoogle Scholar
- Hong CY, Hughes K, Chia KS, Ng V, Ling SL: Urinary alpha1-microglobulin as a marker of nephropathy in type 2 diabetic Asian subjects in Singapore. Diabetes Care. 2003, 26: 338-342. 10.2337/diacare.26.2.338.PubMedGoogle Scholar
- Thomas MC, Burns WC, Cooper ME: Tubular changes in early diabetic nephropathy. Adv Chronic Kidney Dis. 2005, 12: 177-186. 10.1053/j.ackd.2005.01.008.PubMedGoogle Scholar
- Thomson SC, Vallon V, Blantz RC: Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol Renal Physiol. 2006, 286: F8-15. 10.1152/ajprenal.00208.2003.Google Scholar
- Singh DK, Winocour P, Farrington K: Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat Clin Pract Nephrol. 2008, 4: 216-226. 10.1038/ncpneph0757.PubMedGoogle Scholar
- Koomans HA, Blankestijn PJ, Joles JA: Sympathetic hyperactivity in chronic renal failure: A wake-up call. J Am Soc Nephrol. 2004, 15: 524-537. 10.1097/01.ASN.0000113320.57127.B9.PubMedGoogle Scholar
- Perico N, Benigni A, Remuzzi G: Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection. Nat Rev Drug Discov. 2008, 7: 936-953. 10.1038/nrd2685.PubMedGoogle Scholar
- Zeisberg M, Kalluri R: Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease. Pediatr Nephrol. 2008, 23: 1395-1398. 10.1007/s00467-008-0818-x.PubMedGoogle Scholar
- Wang S, Chen Q, Simon TC, Strebeck F, Chaudhary L, Morrissey J, Liapis H, Klahr S, Hruska KA: Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int. 2003, 63: 2037-2049. 10.1046/j.1523-1755.2003.00035.x.PubMedGoogle Scholar
- Leask A, Abraham DJ: TGF-β signaling and the fibrotic response. FASEB J. 2004, 18: 816-827. 10.1096/fj.03-1273rev.PubMedGoogle Scholar
- Xu J, Lamouille S, Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009, 19: 156-172. 10.1038/cr.2009.5.PubMedGoogle Scholar
- Wang SN, Lapage J, Hirschberg R: Glomerular ultrafiltration and apical tubular action of IGF-I, TGF-beta, and HGF in nephrotic syndrome. Kidney Int. 1999, 56: 1247-1251. 10.1046/j.1523-1755.1999.00698.x.PubMedGoogle Scholar
- Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR: Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: downregulation by cAMP. FASEB J. 1999, 13: 1774-1786.PubMedGoogle Scholar
- Okada H, Danoff TM, Kalluri R, Neilson EG: Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol. 1997, 273: F563-574.PubMedGoogle Scholar
- Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, Neilson EG: Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 2002, 61: 1714-1728. 10.1046/j.1523-1755.2002.00333.x.PubMedGoogle Scholar
- Kriz W, Hahnel B, Rosener S, Elger M: Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis. Kidney Int. 1995, 48: 1435-1450. 10.1038/ki.1995.433.PubMedGoogle Scholar
- Phillips AO, Topley N, Morrisey K, Williams JD, Stedman R: Basic fibroblast growth factor stimulates the release of preformed transforming growth factor beta 1 from human proximal tubular cells in the absence of de novo gene transcription or mRNA translation. Lab Invest. 1997, 76: 591-600.PubMedGoogle Scholar
- Bonner JC: Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004, 15: 255-273. 10.1016/j.cytogfr.2004.03.006.PubMedGoogle Scholar
- Weston BS, Wahab NA, Mason RM: CTGF mediates TGF-beta-induced fibronectin matrix deposition by upregulating active alpha5beta1 integrin in human mesangial cells. J Am Soc Nephrol. 2003, 14: 601-610. 10.1097/01.ASN.0000051600.53134.B9.PubMedGoogle Scholar
- Wahab NA, Weston BS, Mason RM: Modulation of the TGFbeta/Smad signaling pathway in mesangial cells by CTGF/CCN2. Exp Cell Res. 2005, 307: 305-314. 10.1016/j.yexcr.2005.03.022.PubMedGoogle Scholar
- Francki A, Bradshaw AD, Bassuk JA, Howe CC, Couser WG, Sage EH: SPARC regulates the expression of collagen type I and transforming growth factor-beta1 in mesangial cells. J Biol Chem. 1999, 274: 32145-32152. 10.1074/jbc.274.45.32145.PubMedGoogle Scholar
- Okada H, Danoff TM, Kalluri R, Neilson EG: Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol. 1997, 273: F563-F574.PubMedGoogle Scholar
- Brown NJ, Vaughan DE, Fogo AB: Aldosterone and PAI-1: implications for renal injury. J Nephrol. 2002, 15: 230-235.PubMedGoogle Scholar
- Biancone L, David S, Della Pietra V, Montrucchio G, Cambi V, Camussi G: Alternative pathway activation of complement by cultured human proximal tubular epithelial cells. Kidney Int. 1994, 45: 451-460. 10.1038/ki.1994.59.PubMedGoogle Scholar
- Tang S, Sheerin NS, Zhou W, Brown Z, Sacks SH: Apical proteins stimulate complement synthesis by cultured human proximal tubular epithelial cells. J Am Soc Nephrol. 1999, 10: 69-76.PubMedGoogle Scholar
- Nangaku M, Pippin J, Couser WG: Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J Am Soc Nephrol. 1999, 10: 2323-2331.PubMedGoogle Scholar
- Nomura A, Morita Y, Maruyama S, Hotta N, Nadai M, Wang L, Hasegawa T, Matsuo S: Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis. Am J Pathol. 1997, 151: 539-547.PubMed CentralPubMedGoogle Scholar
- Hill PA, Lan HY, Nikolic-Paterson DJ, Atkins RC: ICAM-1 directs migration and localization of interstitial leukocytes in experimental glomerulonephritis. Kidney Int. 1994, 45: 32-42. 10.1038/ki.1994.4.PubMedGoogle Scholar
- Ricardo SD, Levinson ME, DeJoseph MR, Diamond JR: Expression of adhesion molecules in rat renal cortex during experimental hydronephrosis. Kidney Int. 1996, 50: 2002-2010. 10.1038/ki.1996.522.PubMedGoogle Scholar
- Ophascharoensuk V, Giachelli CM, Gordon K, Hughes J, Pichler R, Brown P, Liaw L, Schmidt R, Shankland SJ, Alpers CE, Couser WG, Johnson RJ: Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int. 1999, 56: 571-580. 10.1046/j.1523-1755.1999.00580.x.PubMedGoogle Scholar
- Zoja C, Morigi M, Figliuzzi M, Bruzzi I, Oldroyd S, Benigni A, Ronco P, Remuzzi G: Proximal tubular cell synthesis and secretion of endothelin-1 on challenge with albumin and other proteins. Am J Kidney Dis. 1995, 26: 934-941. 10.1016/0272-6386(95)90058-6.PubMedGoogle Scholar
- Largo R, Gómez-Garre D, Soto K, Marrón B, Blanco J, Gazapo RM, Plaza JJ, Egido J: Angiotensin-converting enzyme is upregulated in the proximal tubules of rats with intense proteinuria. Hypertension. 1999, 33: 732-739.PubMedGoogle Scholar
- Benigni A, Remuzzi G: How renal cytokines and growth factors contribute to renal disease progression. Am J Kidney Dis. 2001, 37 (1 Suppl 2): S21-24. 10.1053/ajkd.2001.20734.PubMedGoogle Scholar
- Abe K, Li K, Sacks SH, Sheerin NS: The membrane attack complex, C5b-9, up regulates collagen gene expression in renal tubular epithelial cells. Clin Exp Immunol. 2004, 136: 60-66. 10.1111/j.1365-2249.2004.02411.x.PubMed CentralPubMedGoogle Scholar
- Justo P, Sanz AB, Sanchez-Niño MD, Winkles JA, Lorz C, Egido J, Ortiz A: Cytokine cooperation in renal tubular cell injury: the role of TWEAK. Kidney Int. 2006, 70: 1750-1758. 10.1038/sj.ki.5001866.PubMedGoogle Scholar
- Wolfs TG, Buurman WA, van Schadewijk A, de Vries B, Daemen MA, Hiemstra PS, van 't Veer C: In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol. 2002, 168: 1286-1293.PubMedGoogle Scholar
- Guo G, Morrissey J, McCracken R, Tolley T, Liapis H, Klahr S: Contributions of angiotensin II and tumor necrosis factor-alpha to the development of renal fibrosis. Am J Physiol Renal Physiol. 2001, 280: F777-785.PubMedGoogle Scholar
- Longaretti L, Benigni A: Endothelin receptor selectivity in chronic renal failure. Eur J Clin Invest. 2009, 39 (Suppl 2): 32-37. 10.1111/j.1365-2362.2009.02119.x.PubMedGoogle Scholar
- Kagami S, Border WA, Miller DE, Noble NA: Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest. 1994, 93: 2431-2437. 10.1172/JCI117251.PubMed CentralPubMedGoogle Scholar
- Gilbert RE, Wu LL, Kelly DJ, Cox A, Wilkinson-BERKa JL, Johnston CI, Cooper ME: Pathological expression of renin and angiotensin II in the renal tubule after subtotal nephrectomy. Implications for the pathogenesis of tubulointerstitial fibrosis. Am J Pathol. 1999, 155: 429-440. 10.1016/S0002-9440(10)65139-5.PubMed CentralPubMedGoogle Scholar
- Yang J, Dai C, Liu Y: Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. J Am Soc Nephrol. 2002, 13: 2464-2477. 10.1097/01.ASN.0000031827.16102.C1.PubMedGoogle Scholar
- Ursula C, Brewster MD, Mark A, Perazella MD: The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med. 2004, 116: 263-272. 10.1016/j.amjmed.2003.09.034.Google Scholar
- Zeisberg M, Bonner G, Maeshima Y, Colorado P, Muller GA, Strutz F, Kalluri R: Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am J Pathol. 2001, 159: 1313-1321. 10.1016/S0002-9440(10)62518-7.PubMed CentralPubMedGoogle Scholar
- Yang J, Liu Y: Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001, 159: 1465-1475. 10.1016/S0002-9440(10)62533-3.PubMed CentralPubMedGoogle Scholar
- Liu Y: Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms. Am J Physiol. 1999, 277: F624-633.PubMedGoogle Scholar
- Yang J, Liu Y: Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J Am Soc Nephrol. 2002, 13: 96-107.PubMedGoogle Scholar
- Dworkin LD, Gong R, Tolbert E, Centracchio J, Yano N, Zanabli AR, Esparza A, Rifai A: Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury. Kidney Int. 2004, 65: 409-419. 10.1111/j.1523-1755.2004.00417.x.PubMedGoogle Scholar
- Esposito C, Parrilla B, De Mauri A, Cornacchia F, Fasoli G, Foschi A, Mazzullo T, Plati A, Scudellaro R, Dal Canton A: Hepatocyte growth factor (HGF) modulates matrix turnover in human glomeruli. Kidney Int. 2005, 67: 2143-2150. 10.1111/j.1523-1755.2005.00319.x.PubMedGoogle Scholar
- Vaidya VS, Ferguson MA, Bonventre JV: Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol. 2008, 48: 463-493. 10.1146/annurev.pharmtox.48.113006.094615.PubMed CentralPubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.