Table 2 Main molecular mediators known to participate in the pathophysiological process of tubular degeneration and interstitial fibrosis, grouped according to their most important effect.
From: Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications
ENDOGENOUS ACTIVATORS | ORIGIN | FBR & EMT | INF | TD | ISCH | REFERENCES |
|---|---|---|---|---|---|---|
1. Fibrosis and EMT | ||||||
TGF-β | TC, F, MF, P, iG | X | EMT [252, 253]; secretion of profibrotic MCP-1 [254] and CTGF [255]. Fibrosis: ↑ECM components and PAI, and ↓MMPs [51, 104–106] | |||
EGF | P, UF | X | EMT [256] | |||
FGF | P, UF | X | ||||
PDGF | P, RC | X | Fibroblast to myofibroblast transformation [87], proliferation of myofibroblasts [260] | |||
CTGF | TC | X | X | |||
SPARC | TC, F, MF | X | ↓cell adhesion and proliferation, activates TGF-β and collagen I and fibronectin synthesis [98, 263] | |||
Thrombospondin | TC, F, MF | X | Activates TGF-β [99] | |||
Decorin and biglycan | TC, F, MF | X | ||||
Collagen I | F, MF, TC | X | EMT [264] | |||
PAI-1 | TC, F, MF | X | ECM accumulation and fibrosis [265] | |||
TIMP-1 | TC, F, MF | X | ||||
2. Inflammation | ||||||
Complement C3 and C4 | P, TC | X | X | |||
MCP-1 | TC, P, iG | X | X | |||
ICAM-1 and VCAM-1 | EC, TC | X | On EC: diapedesis and infiltration [270]; On TC: uncertain [271, 272] | |||
Hialuronic acid | TC, F, MF | X | Inflammation, MCP-1 and secretion of adhesion molecules [97, 98] | |||
3. Tubular damage | ||||||
Protein overload | UF | X | Tubule cell activation [65] and release of ET-1 [273], ANG-II [274], MCP-1, and RANTES [275] | |||
Complement C5b-9 | P | X | X | Tubular damage and fibrosis [276] | ||
TNF-α, IFN-γ, Tweak | iWBC | X | X | X | Inflammation, cell death, fibroblast and myofibroblast activation [277–279] | |
4. Ischemia | ||||||
Endothelin-1 | TC | X | X | Vasoconstriction and ischemia [273, 280]; ↑ECM components and TGF-β [87] | ||
RAS | EC, TC, P | X | Vasoconstriction, ischemia and TGF-β secretion [87, 281–284] | |||
ADMA | Plasma | X | X | Vasoconstriction [67] | ||
ENDOGENOUS INHIBITORS | ORIGIN | FBR & EMT | INF | TD | ISCH | REFERENCES |
1. Fibrosis and EMT | ||||||
Collagen IV | F, MF, TC | X | Inhibits EMT [285] | |||
MMP-2 and 9 | TC | X | Degrade collagen IV [286] | |||
HGF | P | X | ||||
BMP-7 | P, TC? | X | Inhibits EMT and fibrosis [285] |