The effect of adipose-derived mesenchymal stem cells on renal function and histopathology in a rat model of ischemia-reperfusion induced acute kidney injury

Document Type : Original Article


1 Department of Physiology, Arak University of Medical Sciences, Arak, Iran

2 Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran

3 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

4 Department of Anatomy, School of Medicine, Arak University of Medical Sciences, Arak, Iran

5 Department of Genetics and Biochemistry, School of Medicine, Arak University of MedicalSciences, Arak, Iran

6 Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

7 Division of Nephrology, Department of Medicine, Saint Louis University, School of Medicine, Saint Louis, Missouri, USA


Objective(s): It has been shown that adipose-derived mesenchymal stem cells (AD-MSC) have protective effects in acute kidney injury (AKI). This study was conducted to assess the therapeutic effects of AD-MSC in rats subjected to acute kidney injury by 45 min of renal ischemia followed by 48 hr of reperfusion (I/R).
Materials and Methods: 28 male Wistar rats were divided into four groups, including control, 48-hr sham, 48-hr I/R, and 48-hr I/R receiving AD-MSC. After 48 hr of reperfusion, blood samples were taken from rats’ hearts, and 24-hr urines were collected using a metabolic cage. Serum creatinine level (Cr), blood urea nitrogen (BUN), creatinine clearance (Ccr), absolute sodium excretion (UNaV°), fractional sodium excretion (FENa), absolute potassium excretion (UKV°), factional potassium excretion (FEK), and urine osmolarity were measured. Malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured in the right kidney, while the left kidney was used for histologic study after Hematoxylin-Eosin staining.
Results: Renal I/R significantly increased serum Cr, BUN, UNaV°, FENa, FEK, and tissue MDA, and significantly decreased Ccr and urine osmolarity as compared with the sham group. Moreover, histologic studies showed that I/R increased Bowman capsule area, tubular necrosis, vascular congestion, and caused formation of intratubular casts. Administration of AD-MSC at the time of I/R completely or partially protected kidneys from these I/R induced injuries.
Conclusion: Our results show that injection of AD-MSC can reduce degree of renal injury caused by 45 min of ischemia followed by 48 hr of reperfusion in rats.


1. Shamsi M, Haghverdi F,Changizi- Ashtiyani S. A brief review of Rhazes, Avicenna, and Jorjani’s views on diagnosis of diseases through urine examination. Iran J Kidney Dis 2014; 8: 278-285.
2. Fan PC, Chen CC, Chen YC, Chang YS, Chu PH. MicroRNAs in acute kidney injury. Hum Genomics 2016; 10: 29-41.
3. Makris K, Spanou L. Acute kidney injury: definition, pathophysiology and clinical phenotypes. Clin Biochem Rev 2016; 37: 85-98.
4. Mahmoudzadeh L, Najafi H, Changizi-Ashtiyani S, Mohamadi Yarijani Z. Anti‐inflammatory and protective effects of saffron extract in ischaemia/reperfusion‐induced acute kidney injury. Nephrology 2017; 22: 748-754.
5. Ferenbach DA, Bonventre JV. Acute kidney injury and chronic kidney disease: From the laboratory to the clinic. Nephrol Ther 2016; 12 Suppl 1: S41- S48.
6. Barnes CJ, Distaso CT, Spitz KM, Verdun VA, Haramati A. Comparison of stem cell therapies for acute kidney injury. Am J Stem Cells 2016; 5: 1-10.
7. Bastani B. The worsening transplant organ shortage in USA; desperate times demand innovative solutions. J Nephropathol 2015; 4: 105-109.
8. Huber-Lang M, Wiegner R, Lampl L, Brenner RE. Mesenchymal stem cells after polytrauma: actor and target. Stem Cells Int 2016; 2016: 6289825.
9. Aghajani Nargesi A, Lerman LO, Eirin A. Mesenchymal stem cell-derived extracellular vesicles for kidney repair: current status and looming challenges. Stem Cell Res Ther 2017; 8: 273.
10.    Shih YC, Lee PY, Cheng H, Tsai CH, Ma H, Tarng DC. Adipose-derived stem cells exhibit anti-oxidative and antiapoptotic properties to rescue ischemic acute kidney injury in rats. Plast Reconstr Surg 2013; 132: 940 e-951e.
11.    Collett JA, Traktuev DO, Mehrotra P, Crone A, Merfeld-Clauss S, March KL, et al. Human adipose stromal cell therapy improves survival and reduces renal inflammation and capillary rarefaction in acute kidney injury. J Cell Mol Med 2017; 21: 1420-1430.
12.    Herrera M, Mirotsou M. Stem cells: Potential and challenges for kidney repair. Am J Physiol Renal Physiol 2014; 306: F12-23.
13.    Hoseini SJ, Ghazavi H, Forouzanfar F, Mashkani B, Ghorbani A, Mahdipour E, et al. Fibroblast growth factor 1-transfected adipose-derived mesenchymal stem cells promote angiogenic proliferation. DNA Cell Biol 2017; 36: 401-412.
14.    Tan J, Hu J, He Y, Cui F. Protective role of silymarin in a mouse model of renal Ischemia-reperfusion injury. Diagn Pathol 2015; 10: 198-203.
15.    Nemoto T, Burne MJ, Daniels F, O’Donnell MP, Crosson J, Berens K, et al. Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure. Kidney Int 2001; 60: 2205-2214.
16.    Naccarato WF, Treuting JJ, Cannon DC. Gravimetric determination of urine volumes. Am J Med Technol 1981; 47: 111-112.
17.    Ashour RH, Saad MA, Sobh MA, Al-Husseiny F, Abouelkheir M, Awad A, et al. Comparative study of allogenic and xenogeneic mesenchymal stem cells on cisplatin-induced acute kidney injury in sprague-dawley rats. Stem Cell Res Ther 2016; 7: 126-142.
18.    Azarkish F, Hashemi K, Talebi A, Kamalinejad M, Soltani N, Pouladian N. Effect of the administration of solanum nigrum fruit on prevention of diabetic nephropathy in streptozotocin-induced diabetic rats. Pharmacognosy Res 2017; 9: 325-332.
19.    Qasem MA, Noordin MI, Arya A, Alsalahi A, Jayash SN. Evaluation of the glycemic effect of ceratonia siliqua pods (Carob) on a streptozotocin-nicotinamide induced diabetic rat model. Peer J 2018; 6: e4788.
20.    Najafi H, Changizi Ashtiyani S, Sayedzadeh SA, Mohamadi Yarijani Z, Fakhri S. Therapeutic effects of curcumin on the functional disturbances and oxidative stress induced by renal ischemia/reperfusion in rats. Avicenna J Phytomed 2015; 5: 576-586.
21.    Sheridan AM, Bonventre JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens 2000; 9: 427-434.
22.    Sheridan AM, Bonventre JV. Pathophysiology of ischemic acute renal failure. Contrib Nephrol 2001; 132: 7-21.
23.    Chen YT, Sun CK, Lin YC, Chang LT, Chen YL, Tsai TH, et al. Adipose-derived mesenchymal stem cell protects kidneys against ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med 2011; 9: 51-67.
24.    Abd Elwahab S, Hussein Ali A, Sayed Mahmoud A, Fathy Ahmed A, Foua d Ahmed R. Bone marrow derived mesenchymalstem cell therapy in Induced acute renal injury in adult male albino rats. J Cytol Histol 2017; 8: 451-458.
25.    Beiral HJ, Rodrigues-Ferreira C, Fernandes AM, Gonsalez SR, Mortari NC, Takiya CM, et al. The impact of stem cells on electron fluxes, proton translocation, and ATP synthesis in kidney mitochondria after ischemia/reperfusion. Cell Transplant 2014; 23: 207-220.
26.    Monsel A, Zhu YG, Gennai S, Hao Q, Liu J, Lee JW. Cell-based therapy for acute organ injury: preclinical evidence and ongoing clinical trials using mesenchymal stem cells. Anesthesiology 2014; 121: 1099-1121.
27.    Shen ZY, Zhang J, Song HL, Zheng WP. Bone-marrow mesenchymal stem cells reduce rat intestinal ischemia-reperfusion injury, ZO-1 downregulation and tight junction disruption via a TNF-alpha-regulated mechanism. World J Gastroenterol 2013; 19: 3583-3595.
28.    Changizi Ashtiyani S, Zohrabi M, Hassanpoor A, Hosseini N, Hajihashemi S. Oral administration of the aqueous extract of rosmarinus officinalis in rats before renal reperfusion injury. Iran J Kidney Dis 2013; 7: 367-375.
29.    Moosavi SM, Bayat G, Owji SM, Panjehshahin MR. Early renal post-ischaemic tissue damage and dysfunction with contribution of A1-adenosine receptor activation in rat. Nephrology (Carlton) 2009; 14: 179-188.
30.    Seguro AC, Shimizu MH, Monteiro JL, Rocha AS. Effect of potassium depletion on ischemic renal failure. Nephron 1989; 51: 350-354.
31.    La Manna G, Bianchi F, Cappuccilli M, Cenacchi G, Tarantino L, Pasquinelli G, et al. Mesenchymal stem cells in renal function recovery after acute kidney injury: use of a differentiating agent in a rat model. Cell Transplant 2011; 20: 1193-1208.
32.    Nakamura K, Komagiri Y, Kubokawa M. Effects of cytokines on potassium channels in renal tubular epithelia. Clin Exp Nephrol 2012; 16: 55-60.
33.    Rowart P, Erpicum P, Detry O, Weekers L, Gregoire C, Lechanteur C, et al. Mesenchymal stromal cell therapy in ischemia/reperfusion injury. J Immunol Res 2015; 2015: 602597.
34.    Yang CC, Chien CT, Wu MH, Ma MC, Chen CF. NMDA receptor blocker ameliorates ischemia-reperfusion-induced renal dysfunction in rat kidneys. Am J Physiol Renal Physiol 2008; 294: F1433- F1440.
35.    Fonseca I, Reguengo H, Almeida M, Dias L, Martins LS, Pedroso S, et al. Oxidative stress in kidney transplantation: malondialdehyde is an early predictive marker of graft dysfunction. Transplantation 2014; 97: 1058-1065.
36.    Moosavi SMS, Changizi-Ashtiyani S, Hosseinkhani S. L‐carnitine improves oxidative stress and suppressed energy metabolism but not renal dysfunction following release of acute unilateral ureteral obstruction in rat. Neurol Urodyn 2011; 30: 480-387.
37.    Zhuo W, Liao L, Xu T, Wu W, Yang S, Tan J. Mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal dysfunction by improving the anti-oxidant/oxidant balance in the ischemic kidney. Urol Int 2011; 86: 191-196.
38.    Zhang Z, Dmitrieva NI, Park JH, Levine RL, Burg MB. High urea and NaCl carbonylate proteins in renal cells in culture and in vivo, and high urea causes 8-oxoguanine lesions in their DNA. Proc Natl Acad Sci U S A 2004; 101: 9491-9496.
39.    Mohammadzadeh M, Halabian R, Gharehbaghian A, Amirizadeh N, Jahanian-Najafabadi A, Roushandeh AM, et al. Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity. Cell Stress Chaperones 2012;17:553-565.
40.    Kim WS, Park BS, Kim HK, Park JS, Kim KJ, Choi JS, et al. Evidence supporting anti-oxidant action of adipose-derived stem cells: protection of human dermal fibroblasts from oxidative stress. J Dermatol Sci 2008; 49: 133-142.
41.    Havasi A, Borkan SC. Apoptosis and acute kidney injury. Kidney Int 2011; 80: 29-40.
42.    Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 2008; 103: 1204-1219.
43.    Glenn JD, Whartenby KA. Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy. World J Stem Cells 2014; 6: 526-539.
44.    Lange C, Togel F, Ittrich H, Clayton F, Nolte-Ernsting C, Zander AR, et al. Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int 2005; 68: 1613-1617.
45.    Patschan D, Buschmann I, Ritter O, Kribben A. Cell-Based therapies in acute kidney injury (AKI). Kidney Blood Press Res 2018; 43: 673-681.
46.    Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 2011; 121: 4210-4221.
47.    Kelly KJ, Williams WW, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, et al. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 1996; 97: 1056-1063.
48.    Hara Y, Stolk M, Ringe J, Dehne T, Ladhoff J, Kotsch K, et al. In vivo effect of bone marrow-derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia. Transpl Int 2011; 24: 1112-1123.
49.    Goligorsky MS, Brodsky SV, Noiri E. Nitric oxide in acute renal failure: NOS versus NOS. Kidney Int 2002; 61: 855-861.
50.    Peresleni T, Noiri E, Bahou WF, Goligorsky MS. Antisense oligodeoxynucleotides to inducible NO synthase rescue epithelial cells from oxidative stress injury. Am J Physiol 1996; 270: F971- F977.
51.    Hagiwara M, Shen B, Chao L, Chao J. Kallikrein-modified mesenchymal stem cell implantation provides enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation. Hum Gene Ther 2008; 19: 807-819.
52.    Borger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, et al. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci 2017; 18: 1450-1468.
53.    Song Y, Peng C, Lv S, Cheng J, Liu S, Wen Q, et al. Adipose-derived stem cells ameliorate renal interstitial fibrosis through inhibition of EMT and inflammatory response via TGF-β1 signaling pathway. Int Immunopharmacol 2017; 44: 115-122.
54.    Eirin A, Zhu XY, Krier JD, Tang H, Jordan KL, Grande JP, et al. Adipose tissue‐derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells 2012; 30: 1030-1041.
55.    Sheashaa H, Lotfy A, Elhusseini F, Aziz AA, Baiomy A, Awad S, et al. Protective effect of adipose-derived mesenchymal stem cells against acute kidney injury induced by ischemia-reperfusion in Sprague-Dawley rats. Exp Ther Med 2016; 11: 1573-1580.