Adipose-Derived Mesenchymal Stem Cell Protects Kidneys against Ischemia-Reperfusion Injury through Suppressing Oxidative Stress and Inflammatory Reaction
- Yen-Ta Chen†1,
- Cheuk-Kwan Sun2, 10,
- Yu-Chun Lin†3, 4,
- Li-Teh Chang5,
- Yung-Lung Chen3,
- Tzu-Hsien Tsai3,
- Sheng-Ying Chung3,
- Sarah Chua3,
- Ying-Hsien Kao6,
- Chia-Hung Yen7,
- Pei-Lin Shao8,
- Kuan-Cheng Chang9,
- Steve Leu†3, 4 and
- Hon-Kan Yip†3, 4Email author
© Chen et al; licensee BioMed Central Ltd. 2011
Received: 10 January 2011
Accepted: 5 May 2011
Published: 5 May 2011
Reactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR) injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury.
Adult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus immediate intra-renal administration of 1.0 × 106 autologous ADMSCs, followed by intravenous ADMSCs at 6 h and 24 h after IR). The duration of ischemia was 1 h, followed by 72 hours of reperfusion before the animals were sacrificed.
Serum creatinine and blood urea nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p < 0.03). The mRNA expressions of inflammatory, oxidative stress, and apoptotic biomarkers were lower, whereas the anti-inflammatory, anti-oxidative, and anti-apoptotic biomarkers were higher in group 3 than in group 2 (all p < 0.03). Immunofluorescent staining showed a higher number of CD31+, von Willebrand Factor+, and heme oxygenase (HO)-1+ cells in group 3 than in group 2 (all p < 0.05). Western blot showed notably higher NAD(P)H quinone oxidoreductase 1 and HO-1 activities, two indicators of anti-oxidative capacity, in group 3 than those in group 2 (all p < 0.04). Immunohistochemical staining showed higher glutathione peroxidase and glutathione reductase activities in group 3 than in group 2 (all p < 0.02)
ADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response.
N ot only is ischemia-reperfusion (IR) injury of the kidney encountered in patients with contrast media-induced nephropathy  and in those with shock followed by resuscitation in the emergency and intensive care settings , but it is also a common early event in kidney transplantation that contributes to organ dysfunction . The manifestations include acute tubular-epithelial damage [4, 5], loss of peri-tubular microvasculature , as well as inflammation and leukocyte infiltration [3–5, 7]. Despite current advances in medical treatment, IR injury of the kidney, which is a common cause of acute renal failure, remains a major healthcare problem with high rates of in-hospital mortality and morbidity [4, 8, 9]. This situation warrants the development of new treatment modalities .
Growing data have shed considerable light on the effectiveness and safety of mesenchymal stem cell (MSC) treatment in improving ischemia-related organ dysfunction [7, 10–12]. Indeed, the therapeutic potential of MSC has been extensively investigated using animal models of kidney disease [7, 10, 11, 13]. Interestingly, although several experimental studies [6, 7, 10, 11, 13–15] have established the role of MSC therapy in preserving renal parenchymal integrity from acute ischemic injury and improving kidney function from acute damage through engraftment of MSCs in both glomerular and tubular structures, regeneration of tubular epithelium, augmentation of paracrine and systemic secretory functions, and enhancement of peri-tubular capillary regeneration, the precise mechanisms underlying the improvement in kidney function remain unclear. Furthermore, despite the availability of various cellular sources for experimental investigations [6, 7, 10–15] including bone marrow-derived mesenchymal stem cells (BMDMSCs), hematopoietic stem/progenitor cells, and cells of embryonic origins, the ethical issue regarding the source and safety of allo- and xeno-grafting has become important concern in the clinical setting. On the other hand, the use of adipose-derived (AD) MSCs has the distinct advantages of minimal invasiveness in harvesting and unlimited supply from in vitro culturing . In addition, the paracrine characteristics of ADMSCs have been shown to be different from those of bone marrow origin with the former showing more potent anti-inflammatory and immuno-modulating functions . Moreover, although it has been reported that the complicated mechanisms underlying IR injuries of solid organs involve the generation of reactive oxygen species (ROS), mitochondrial damage [18, 19], apoptosis , and a cascade of inflammatory processes , the impact of MSCs treatment on these cellular and molecular changes [6, 7, 18, 19] during renal IR injury remains to be elucidated. Therefore, we hypothesized that administration of ADMSCs is beneficial in alleviating IR injury of the kidney through ameliorating anti-inflammatory response and oxidative stress as well as preserving the integrity of peri-tubular microvasculature.
All experimental animal procedures were approved by the Institute of Animal Care and Use Committee at our hospital and performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, National Academy Press, Washington, DC, USA, revised 1996).
Animal Grouping and Isolation of Adipose-Derived Mesenchymal Stem Cells
Pathogen-free, adult male Sprague-Dawley (SD) rats (n = 24) weighing 275-300 g (Charles River Technology, BioLASCO Taiwan Co., Ltd., Taiwan) were randomized into group 1 (sham control), group 2 (IR plus culture medium) and group 3 (IR plus autologous ADMSC implantation) before isolation of ADMSCs.
The rats in group 3 (n = 8) were anesthetized with inhalational isoflurane 14 days before induction of IR injury. Adipose tissue surrounding the epididymis was carefully dissected and excised. Then 200-300 μL of sterile saline was added to every 0.5 g of tissue to prevent dehydration. The tissue was cut into <1 mm3 size pieces using a pair of sharp, sterile surgical scissors. Sterile saline (37°C) was added to the homogenized adipose tissue in a ratio of 3:1 (saline: adipose tissue), followed by the addition of stock collagenase solution to a final concentration of 0.5 units/mL. The centrifuge tubes with the contents were placed and secured on a Thermaline shaker and incubated with constant agitation for 60 ± 15 minutes at 37°C. After 40 minutes of incubation, the content was triturated with a 25 mL pipette for 2-3 minutes. The cells obtained were placed back to the rocker for incubation. The contents of the flask were transferred to 50 mL tubes after digestion, followed by centrifugation at 600 g for 5 minutes at room temperature. The lipid layer and saline supernatant from the tube were poured out gently in one smooth motion or removed using vacuum suction. The cell pellet thus obtained was resuspended in 40 mL saline and then centrifuged again at 600 g for 5 minutes at room temperature. After being resuspended again in 5 mL saline, the cell suspension was filtered through a 100 mm filter into a 50 mL conical tube to which 2 mL of saline was added to rinse the remaining cells through the filter. The flow-through was pipetted into a new 50 mL conical tube through a 40 mm filter. The tubes were centrifuged for a third time at 600 g for 5 minutes at room temperature. The cells were resuspended in saline. An aliquot of cell suspension was then removed for cell culture in DMEM-low glucose medium containing 10% FBS for 14 days. Approximately 5.5 × 106 ADMSCs were obtained from each rat.
Flow Cytometric Characterization of ADMSCs
ADMSC Labeling, Protocol of IR Induction, and Rationale of Timing for ADMSC Administration
On day 14, CM-Dil (Vybrant™ Dil cell-labeling solution, Molecular Probes, Inc.) (50 μg/ml) was added to the culture medium 30 minutes before IR procedure for ADMSC labeling. The procedures of CM-Dil staining for ADMSC were performed based on our previous study . After completion of ADMSC labeling, all animals were anesthetized by chloral hydrate (35 mg/kg i.p.) plus inhalational isoflurane and placed in a supine position on a warming pad at 37°C. Renal IR was then conducted in group 2 and group 3 animals on which a midline laparotomy was performed. Bilateral renal pedicles were clamped for one hour using non-traumatic vascular clips before reperfusion for 72 hours. Normal controls without renal IR (i.e. group 1) were subjected to laparotomy only.
Previous experimental study  has demonstrated that administration of mesenchymal stem cells either immediately or 24 h after IR-induced acute renal failure has significantly improved renal function and alleviated renal injury. In addition, we have recently shown that administration of ADMSCs to the rats at 6-hour intervals after acute ischemic stroke significantly improved organ damage . Thus, the timing for ADMSC administration in the current study was based on these studies.
In group 2 animals, intra-renal injection of 35 μL of culture medium was performed one hour after reperfusion, followed by intra-venous injection of 35 μL culture medium at 6 and 24 hours after IR procedure through the penile vein. Group 3 animals followed the same protocol, except for that equal volume of culture medium with ADMSCs (1.0 × 106) was administered at each time point instead of pure culture medium as in group 2. For the study purpose, animals were sacrificed at day 1 (n = 6), day 3 (n = 8) and day 14 (n = 6) after IR procedure. The kidneys were collected for subsequent studies.
Determination of Renal Function
Serum levels of creatinine and blood urea nitrogen (BUN) were measured in all three groups of rats prior to IR procedure and at 24 h, 72 h, and day 14 after the IR procedure before sacrificing the animals (n = 6 for each group). Additionally, urine protein and creatinine levels were also measured in all animals at these time points. Twenty-four hour urine was collected from the study animals for estimating daily urine volume and measuring the ratio of urine protein to urine creatinine excretion. Quantification of urine protein, BUN, and creatinine level was performed using standard laboratory equipment at our hospital.
Hematoxylin and Eosin (H & E) Staining and Histopathology Scoring
Kidney specimens from all animals were fixed in 10% buffered formalin before embedding in paraffin. Tissue was sectioned at 5 mm and then stained with hematoxylin and eosin for light microscopic analysis. Histopathology scoring was applied based on a previous study  in a blind fashion. The score was given based on grading of tubular necrosis, loss of brush border, cast formation, and tubular dilatation in 10 randomly chosen, non-overlapping fields (200×) as follows: 0 (none), 1 (≤10%), 2 (11-25%), 3 (26-45%), 4 (46-75%), and 5 (≥76%).
Immunofluorescent and Immunohistochemical (IHC) Studies
CM-Dil-positive ADMSCs engrafted in the renal parenchyma after transplantation were identified through immunofluorescent staining that was also used for the examination of heme oxygenase (HO)-1-, CD31-, or vWF-positive cells using respective primary antibody. Moreover, IHC labeling technique was adopted for identifying glutathione peroxidase (GPx)- and glutathione reductase (GR)-positive cells using respective primary antibodies based on our recent study . Irrelevant antibodies were used as controls in the current study.
An IHC-based scoring system was utilized for semiquantitative analyses of GR and GPx as percentage of positive cells in a blind fashion [Score of positively-stained cell for GR and GPx: 0 = no stain %; 1 = <15%; 2 = 15-25%; 3 = 25-50%; 4 = 50-75%; 5 = >75-100% per high-power filed (200 ×)].
Western Blot Analysis for Oxidative Stress, Nuclear Factor (NF)-κB, Intercellular Adhesion Molecule (ICAM)-1, HO-1, NAD(P)H Quinone Oxidoreductase (NQO)1 in Kidney
Equal amounts (10-30 mg) of protein extracts from kidney were loaded and separated by SDS-PAGE using 8-10% acrylamide gradients. Following electrophoresis, the separated proteins were transferred electrophoretically to a polyvinylidene difluoride (PVDF) membrane (Amersham Biosciences). Nonspecific proteins were blocked by incubating the membrane in blocking buffer (5% nonfat dry milk in T-TBS containing 0.05% Tween 20) overnight. The membranes were incubated with the indicated primary antibodies (GR, 1: 1000, Abcam; NQO1, 1: 1000, Abcam; GPx, 1: 2000, Abcam; HO-1, 1: 250, Abcam; ICAM-1, 1: 2000, Abcam; NF-κB [p65], 1: 200, Santa Cruz; Actin 1: 10000, Chemicon) for 1 hour at room temperature. Horseradish peroxidase-conjugated anti-rabbit immunoglobulin IgG (1: 2000, Cell signaling) was used as a second antibody for 1 hour at room temperature. The washing procedure was repeated eight times within one hour.
The Oxyblot Oxidized Protein Detection Kit was purchased from Chemicon (S7150). The procedure of 2,4-dinitrophenylhydrazine (DNPH) derivatization was carried out on 6 μg of protein for 15 minutes according to manufacturer's instructions. One-dimensional electrophoresis was performed on 12% SDS/polyacrylamide gel after DNPH derivatization. Proteins were transferred to nitrocellulose membranes which were then incubated in the primary antibody solution (anti-DNP 1: 150) for two hours, followed by incubation with secondary antibody solution (1:300) for one hour at room temperature. The washing procedure was repeated eight times within 40 minutes.
Immunoreactive bands were visualized by enhanced chemiluminescence (ECL; Amersham Biosciences) which was then exposed to Biomax L film (Kodak). For quantification, ECL signals were digitized using Labwork software (UVP). For oxyblot protein analysis, a standard control was loaded on each gel.
Real-Time Quantitative PCR Analysis
Real-time polymerase chain reaction (PCR) was conducted using LightCycler TaqMan Master (Roche, Germany) in a single capillary tube according to the manufacturer's guidelines for individual component concentrations as we previously reported [12, 20]. Forward and reverse primers were each designed based on individual exons of the target gene sequence to avoid amplifying genomic DNA.
During PCR, the probe was hybridized to its complementary single-strand DNA sequence within the PCR target. As amplification occurred, the probe was degraded due to the exonuclease activity of Taq DNA polymerase, thereby separating the quencher from reporter dye during extension. During the entire amplification cycle, light emission increased exponentially. A positive result was determined by identifying the threshold cycle value at which reporter dye emission appeared above background.
Quantitative data are expressed as means ± SD. Statistical analysis was adequately performed by ANOVA followed by Bonferroni multiple-comparison post hoc test. Statistical analysis was performed using SAS statistical software for Windows version 8.2 (SAS institute, Cary, NC). A probability value <0.05 was considered statistically significant.
Serial Changes in Serum Levels of Creatinine and BUN, Urine Amount and the Ratio of Urine Protein to Creatinine after IR Procedure
The daily urine amount did not differ among groups 1, 2, and 3 at 24 h after IR procedure (Figure 2C). However, the amounts were remarkably increased in group 3 as compared with group 2 at 72 h and day 14 after IR procedure. Conversely, the ratio of urine protein to urine creatinine was notably lower in group 3 than in group 2 at 24 h and 72 h after IR (Figure 2D). However, the ratios were similar between groups 2 and 3 at day 14 after IR procedure.
Histopathological Scoring of the Kidneys
Identification of ADMSC Engrafted into Renal Parenchyma and CD31+ and von Willebrand Factor (vWF)+ Cells in Peri-tubular Regions
Changes in mRNA Expression of Vasoactive, Inflammatory, Anti-oxidative, and Apoptotic Mediators in Renal Parenchyma after IR Injury
Relative changes in mRNA expression of vasoactive, inflammatory, anti-oxidative, and apoptotic mediators in renal parenchyma after IR injury
Group 1 (n = 8)
Group 2 (n = 8)
Group 3 (n = 8)
2.38 ± 0.48†
1.81 ± 0.34‡
Tumor necrosis factor-α
2.29 ± 0.25†
1.80 ± 0.20‡
1.48 ± 0.14†
1.19 ± 0.09‡
endothelial nitric oxide synthase
0.62 ± 0.19†
0.89 ± 0.16‡
2.06 ± 0.37†
2.86 ± 0.50‡
0.50 ± 0.13†
0.75 ± 0.13‡
1.89 ± 0.62†
2.76 ± 0.88‡
1.67 ± 0.25†
2.54 ± 0.64‡
1.83 ± 0.39†
2.82 ± 0.98‡
0.74 ± 0.09†
0.94 ± 0.10‡
2.01 ± 0.20†
1.53 ± 0.14‡
The mRNA expressions of tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP)-9, two indicators of inflammation, were remarkably higher in group 2 than in groups 1 and 3, and notably higher in group 3 than in group 1 (Table 1). On the other hand, the mRNA expressions of endothelial nitric oxide synthase (eNOS), IL-10, adiponectin, the anti-inflammatory indexes, were notably lower in group 2 than in group 3 (Table 1). These findings imply that ADMSC therapy inhibited inflammatory reaction in this experimental setting.
The mRNA expressions of NQO1, GR, and GPx, three anti-oxidative indicators, were remarkably lower in group 1 than in groups 2 and 3, and notably lower in group 2 than in group 3 (Table 1). These findings suggest an anti-oxidative response after induction of IR injury and an enhancement of anti-oxidant effect following ADMSC administration.
The mRNA expression of caspase 3, an index of apoptosis, was notably higher in group 2 than in groups 1 and 3, and markedly higher in group 3 than in group 1 (Table 1). In contrast, the mRNA expression of Bcl-2, an index of anti-apoptosis, was remarkably lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1 (Table 1). These findings imply that ADMSC treatment exerted anti-apoptotic effects.
Protein Expressions of Inflammatory and Anti-oxidative Mediators in Renal Parenchyma after IR Injury
The protein expression of NQO1 (Figure 7C), another anti-oxidative biomarker, was remarkably lower in group 2 than in groups 1 and 3, and significantly lower in group 1 than in group 3 at 24 h and 72 h after IR injury. On the other hand, this protein expression was markedly lower in group 1 than in groups 2 and 3, and notably lower in group 2 than in group 3 at day 14 after IR injury.
Findings from Immunofluorescent and IHC Staining
This study, which used a rat model to investigate the therapeutic impact of ADMSC therapy on IR-induced acute kidney injury, provided several striking implications. First, ADMSC treatment significantly preserved architectural integrity of renal parenchyma and attenuated the deterioration of renal function after IR injury. Second, ADMSC therapy initiated early-onset anti-inflammatory and anti-oxidative effects. Third, the transplanted ADMSCs participated in angiogenesis early after IR injury.
Stem Cell Therapy Effectively Protected Renal Function from Acute Kidney Injury--Complete Mechanisms Remain Poorly Defined
Surprisingly, while studies on animal models [6, 7, 10, 11, 13] have emphasized stem cell therapy as an effective treatment modality for acute kidney injury, the mechanistic basis underlying the observed improvement in renal function after stem cell therapy has not been extensively explored. In fact, the majority of previous studies [6, 7, 10–15] have focused on investigating one particular mechanism rather than a complete picture. The mechanisms having been established by previous studies included angiogenesis, stem cell homing, anti-inflammatory reaction, anti-oxidative stress, and immunomodulation [6, 7, 10–15, 23]. The actual mechanisms underlying the improvement of renal function following ADMSC therapy could be even more complex . The significance of a single mechanism within the whole picture, however, is still unclear .
ADMSC Transplantation Attenuates Inflammatory Response, Suppresses Oxidative Stress, and Limits Cellular Apoptosis and Architectural Damage in Kidney Following Acute IR Injury--Impact of Immune Modulation
Numerous studies [6, 7, 24] have shown that acute IR injury elicits rigorous inflammatory response and enhances generation of ROS and free radicals which, in turn, cause the damage of renal parenchyma and destroy the architectural integrity of the kidney. One important finding in the current study is that the mRNA expressions of TNF-1α and MMP-9 as well as the protein expressions of ICAM-1, NF-κB, and oxidative stress were remarkably increased in group 2 compared to normal controls after acute IR injury. In this way, our findings reinforce those of previous studies [6, 7, 24]. Of importance is that, as compared with IR-injured animals without treatment, the expressions of these inflammatory and oxidative biomarkers at both gene and protein levels were significantly suppressed in animals following ADMSC administration. Accumulating evidence has demonstrated that MSCs have distinctive immunomodulatory property that contributes to the down-regulation of inflammatory reaction in ischemic condition [16, 20, 25]. Therefore, our findings are consistent with those of previous studies [16, 20, 25].
There are several key findings in the current study. Immunofluorescent and IHC staining as well as Western blot analysis demonstrated remarkably suppressed expressions of NQO1 and HO-1, the scavengers for free radicals, in group 2 and significant restoration in group 3 after ADMSC treatment. Besides, significant reduction was noted in the expressions of anti-oxidative enzymes GR and GPx in group 2 after IR injury, whereas the expressions were notably enhanced in group 3 following ADMSC therapy. In addition, significantly reduced mRNA expression of caspase-3 and notably enhanced mRNA expressions of Bcl-2 were demonstrated in IR-injured animals with ADMSC treatment compared with those without. Importantly, histological and serum biochemical findings showed, respectively, that renal parenchymal damage and renal dysfunction were substantially improved in group 3 following ADMSC treatment. Taken together, these findings suggest that ADMSC treatment preserved renal function, at least in part, through inhibiting inflammatory reactions, reducing apoptosis, and suppressing oxidative stress in this experimental setting of acute kidney IR injury.
The cause of discrepancy between mRNA and protein expressions of HO-1 on both day 1 and day 3 after IR remains unknown. We propose that it may be due to post-transcriptional regulation (i.e. speed of translation or degradation of HO-1) on mRNA and protein expression levels or the change in speed of protein degradation. Previous study by Mahin et al.  showed a synchronized up-regulation of HO-1 mRNA and protein levels at acute phase after IR. Thus, our results on mRNA expression rather than protein expression of HO-1 were consistent with their findings. Another possible explanation may be that the microsomal fraction was utilized for Western blot analysis in the study by Mahin et al. , whereas whole cell lysates were used for Western blot in our study. Since alternation in sub-cellular distribution of HO-1 has been reported in cell under stress , we speculate that the increased protein expression of HO-1 in the microsomal fraction of kidneys following IR injury  may be due to translocation of HO-1.
Enhanced Angiogenesis through ADMSC Transplantation--An Ischemia-Relieving Phenomenon Accounting for Tubular Regeneration
This study has limitations. First, since the present study focused on the therapeutic impact of ADMSC on acute renal injury using a rodent model of renal IR, the effects of ADMSC administration were followed only up to 14 days after IR injury without looking into the chronic influence of treatment. Second, although our findings are promising, the underlying mechanisms (Figure 10) involved in ADMSC therapy against renal IR injury remains descriptive. Further investigations, therefore, are warranted to clarify the exact mechanisms involved.
ADMSC markedly improved renal function after acute IR injury. The key mechanisms underlying the positive therapeutic impact of ADMSC treatment on renal function could be due to suppression of inflammatory response and oxidative stress as well as enhancement of angiogenesis.
This study was supported by a program grant from Chang Gung Memorial Hospital, Chang Gung University (grant no. CMRPG 881181).
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