Bone marrow-derived mesenchymal stem cells protect against cisplatin-induced acute kidney injury in rats by inhibiting cell apoptosis

Qi,Shaohua; Wu,Dongcheng

doi:10.3892/ijmm.2013.1517

Bone marrow-derived mesenchymal stem cells protect against cisplatin-induced acute kidney injury in rats by inhibiting cell apoptosis

Authors:
- Shaohua Qi
- Dongcheng Wu
View Affiliations

Affiliations: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: October 8, 2013 https://doi.org/10.3892/ijmm.2013.1517
Pages: 1262-1272
Copyright: © Qi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute kidney injury (AKI) is a common syndrome with a high mortality and morbidity rate. Recent developments in stem cell research have shown great promise for the treatment of AKI. The aim of this study was to investigate the therapeutic potential and anti-apoptotic mechanisms of action of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of AKI induced by cisplatin in vivo and in vitro. In vivo, adult male Sprague-Dawley rats (n=24) were administered BM-MSCs intravenously one day after cisplatin injection. The rats were sacrificed four days after the cisplatin injection and the effects of BM-MSCs on cisplatin-induced AKI, as well as the anti-apoptotic mechanisms involved were investigated. In vitro, NRK-52E cells, a rat renal proximal tubular cell line, were incubated in conditioned medium or complete medium in the presence or absence of cisplatin, followed by cell proliferation and apoptosis assays. The infusion of BM-MSCs preserved renal function, ameliorated renal tubular lesions, reduced apoptosis and accelerated tubular cell regeneration in the rats with cisplatin-induced AKI. The infusion of BM-MSCs also inhibited the activation of two mitogen-activated protein kinases, p38 and ERK, downregulated the expression of Bax and cleaved caspase-3, and upregulated the expression of Bcl-2. BM-MSC-conditioned medium improved NRK-52E cell viability and inhibited apoptosis. In conclusion, our results demonstrate that injecting rats with BM-MSCs protects renal function and structure in cisplatin-induced AKI by inhibiting cell apoptosis in vivo. BM-MSC-conditioned medium protects renal cells from apoptosis induced by cisplatin in vitro. Hence, the infusion of BM-MSCs should be considered as a possible therapeutic strategy for the treatment of AKI.

View Figures

View References

1	Bagshaw SM: Short- and long-term survival after acute kidney injury. Nephrol Dial Transplant. 23:2126–2128. 2008. View Article : Google Scholar : PubMed/NCBI
2	Chertow GM, Burdick E, Honour M, Bonventre JV and Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 16:3365–3370. 2005. View Article : Google Scholar : PubMed/NCBI
3	Tögel FE and Westenfelder C: Kidney protection and regeneration following acute injury: progress through stem cell therapy. Am J Kidney Dis. 60:1012–1022. 2012.PubMed/NCBI
4	Waikar SS, Liu KD and Chertow GM: Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol. 3:844–861. 2008. View Article : Google Scholar : PubMed/NCBI
5	Chen YT, Sun CK, Lin YC, et al: Adipose-derived mesenchymal stem cell protects kidneys against ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med. 9:512011. View Article : Google Scholar
6	Lange C, Togel F, Ittrich H, et al: Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int. 68:1613–1617. 2005. View Article : Google Scholar : PubMed/NCBI
7	Tögel F, Hu Z, Weiss K, Isaac J, Lange C and Westenfelder C: Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 289:F31–F42. 2005.
8	Morigi M, Imberti B, Zoja C, et al: Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol. 15:1794–1804. 2004. View Article : Google Scholar : PubMed/NCBI
9	Morigi M, Introna M, Imberti B, et al: Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cells. 26:2075–2082. 2008. View Article : Google Scholar : PubMed/NCBI
10	Morigi M, Rota C, Montemurro T, et al: Life-sparing effect of human cord blood-mesenchymal stem cells in experimental acute kidney injury. Stem Cells. 28:513–522. 2010.PubMed/NCBI
11	Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM and Camussi G: Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med. 14:1035–1041. 2004.PubMed/NCBI
12	Herrera MB, Bussolati B, Bruno S, et al: Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int. 72:430–441. 2007. View Article : Google Scholar : PubMed/NCBI
13	Lazzeri E, Crescioli C, Ronconi E, et al: Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. J Am Soc Nephrol. 18:3128–3138. 2007. View Article : Google Scholar : PubMed/NCBI
14	Rota C, Imberti B, Pozzobon M, et al: Human amniotic fluid stem cell preconditioning improves their regenerative potential. Stem Cells Dev. 21:1911–1923. 2012. View Article : Google Scholar : PubMed/NCBI
15	Li L, Black R, Ma Z, Yang Q, Wang A and Lin F: Use of mouse hematopoietic stem and progenitor cells to treat acute kidney injury. Am J Physiol Renal Physiol. 302:F9–F19. 2011. View Article : Google Scholar : PubMed/NCBI
16	Horwitz EM, Le Blanc K, Dominici M, et al: Clarification of the nomenclature for MSC: the international society for cellular therapy position statement. Cytotherapy. 7:393–395. 2005. View Article : Google Scholar : PubMed/NCBI
17	Jia X, Xie X, Feng G, et al: Bone marrow-derived cells can acquire renal stem cells properties and ameliorate ischemia-reperfusion induced acute renal injury. BMC Nephrology. 13:1052012. View Article : Google Scholar : PubMed/NCBI
18	Yadav N, Rao S, Bhowmik DM and Mukhopadhyay A: Bone marrow cells contribute to tubular epithelium regeneration following acute kidney injury induced by mercuric chloride. Indian J Med Res. 136:211–220. 2012.
19	Bonegio R and Lieberthal W: Role of apoptosis in the pathogenesis of acute renal failure. Curr Opin Nephrol Hypertens. 11:301–308. 2002. View Article : Google Scholar : PubMed/NCBI
20	Havasi A and Borkan SC: Apoptosis and acute kidney injury. Kidney Int. 80:29–40. 2011. View Article : Google Scholar
21	Yuan L, Wu MJ, Sun HY, et al: VEGF-modified human embryonic mesenchymal stem cell implantation enhances protection against cisplatin-induced acute kidney injury. Am J Physiol Renal Physiol. 300:F207–F218. 2011. View Article : Google Scholar
22	Jo SK, Cho WY, Sung SA, Kim HK and Won NH: MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis. Kidney Int. 67:458–466. 2005. View Article : Google Scholar : PubMed/NCBI
23	Ramesh G and Reeves WB: p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol. 289:F166–F174. 2005. View Article : Google Scholar : PubMed/NCBI
24	Jiang M, Wei Q, Wang J, et al: Regulation of PUMA-alpha by p53 in cisplatin-induced renal cell apoptosis. Oncogene. 25:4056–4066. 2006. View Article : Google Scholar : PubMed/NCBI
25	Wan JX, Zou ZH, You DY, Cui J and Pan YB: Bone marrow-derived mesenchymal stem cells differentiation into tubular epithelial-like cells in vitro. Cell Biochem Funct. 30:129–138. 2012. View Article : Google Scholar : PubMed/NCBI
26	Bi B, Schmitt R, Israilova M, Nishio H and Cantley LG: Stromal cells protect against acute tubular injury via an endocrine effect. J Am Soc Nephrol. 18:2486–2496. 2007. View Article : Google Scholar : PubMed/NCBI
27	Haynesworth SE, Baber MA and Caplan AI: Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol. 166:585–592. 1996. View Article : Google Scholar : PubMed/NCBI
28	Weimar IS, Miranda N, Muller EJ, et al: Hepatocyte growth factor/scatter factor (HGF/SF) is produced by human bone marrow stromal cells and promotes proliferation, adhesion and survival of human hematopoietic progenitor cells (CD34⁺). Exp Hematol. 26:885–894. 1998.
29	Kim JH, Park DJ, Yun JC, et al: Human adipose tissue-derived mesenchymal stem cells protect kidneys from cisplatin nephrotoxicity in rats. Am J Physiol Renal Physiol. 302:F1141–F1150. 2012. View Article : Google Scholar : PubMed/NCBI
30	Zarjou A, Kim J, Traylor AM, et al: Paracrine effects of mesenchymal stem cells in cisplatin-induced renal injury require heme oxygenase-1. Am J Physiol Renal Physiol. 300:F254–F262. 2011. View Article : Google Scholar : PubMed/NCBI
31	Yasuda H, Kato A, Miyaji T, Zhou H, Togawa A and Hishida A: Insulin-like growth factor-I increases p21 expression and attenuates cisplatin-induced acute renal injury in rats. Clin Exp Nephrol. 8:27–35. 2004. View Article : Google Scholar : PubMed/NCBI
32	Nemmar A, Al-Salam S, Zia S, Yasin J, Al Husseni I and Ali BH: Diesel exhaust particles in the lung aggravate experimental acute renal failure. Toxicol Sci. 113:267–277. 2010. View Article : Google Scholar : PubMed/NCBI
33	Du H, Yao W, Fang M and Wu D: ARF triggers cell G1 arrest by a P53 independent ERK pathway. Mol Cell Biochem. 357:415–422. 2011. View Article : Google Scholar : PubMed/NCBI
34	Tsuruya K, Yotsueda H, Ikeda H, et al: Involvement of p53-transactivated Puma in cisplatin-induced renal tubular cell death. Life Sci. 83:550–556. 2008. View Article : Google Scholar : PubMed/NCBI
35	Dominici M, Le Blanc K, Mueller I, et al: Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar
36	Sheikh-Hamad D, Cacini W, Buckley AR, et al: Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. Arch Toxicol. 78:147–155. 2004. View Article : Google Scholar : PubMed/NCBI
37	Dill T, Schachinger V, Rolf A, et al: Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J. 157:541–547. 2009.
38	Drexler H, Meyer GP and Wollert KC: Bone-marrow-derived cell transfer after ST-elevation myocardial infarction: lessons from the BOOST trial. Nat Clin Pract Cardiovasc Med. 3(Suppl 1): S65–S68. 2006. View Article : Google Scholar : PubMed/NCBI
39	Deng YB, Liu XG, Liu ZG, Liu XL, Liu Y and Zhou GQ: Implantation of BM mesenchymal stem cells into injured spinal cord elicits de novo neurogenesis and functional recovery: evidence from a study in rhesus monkeys. Cytotherapy. 8:210–214. 2006. View Article : Google Scholar : PubMed/NCBI
40	Li Y, Chen J, Zhang CL, et al: Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia. 49:407–417. 2005. View Article : Google Scholar : PubMed/NCBI
41	Ezquer F, Ezquer M, Simon V, et al: Endovenous administration of bone marrow-derived multipotent mesenchymal stromal cells prevents renal failure in diabetic mice. Biol Blood Marrow Transplant. 15:1354–1365. 2009. View Article : Google Scholar
42	Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yañez AJ and Conget PA: Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant. 14:631–640. 2008. View Article : Google Scholar : PubMed/NCBI
43	Lieberthal W, Triaca V and Levine J: Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol. 270:F700–F708. 1996.PubMed/NCBI
44	Ramesh G and Reeves WB: TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am J Physiol Renal Physiol. 285:F610–F618. 2003. View Article : Google Scholar : PubMed/NCBI
45	Liu H and Baliga R: Cytochrome P450 2E1 null mice provide novel protection against cisplatin-induced nephrotoxicity and apoptosis. Kidney Int. 63:1687–1696. 2003. View Article : Google Scholar : PubMed/NCBI
46	Hamar P, Song E, Kokeny G, Chen A, Ouyang N and Lieberman J: Small interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury. Proc Natl Acad Sci USA. 101:14883–14888. 2004. View Article : Google Scholar : PubMed/NCBI
47	Price PM, Safirstein RL and Megyesi J: Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am J Physiol Renal Physiol. 286:F378–F384. 2004. View Article : Google Scholar : PubMed/NCBI
48	Santos NA, Bezerra CS, Martins NM, Curti C, Bianchi ML and Santos AC: Hydroxyl radical scavenger ameliorates cisplatin-induced nephrotoxicity by preventing oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Cancer Chemother Pharmacol. 61:145–155. 2008. View Article : Google Scholar
49	Owens DM and Keyse SM: Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene. 26:3203–3213. 2007. View Article : Google Scholar : PubMed/NCBI
50	Dhillon AS, Hagan S, Rath O and Kolch W: MAP kinase signalling pathways in cancer. Oncogene. 26:3279–3290. 2007. View Article : Google Scholar : PubMed/NCBI
51	Rodriguez-Garcia ME, Quiroga AG, Castro J, Ortiz A, Aller P and Mata F: Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells. Toxicol Sci. 111:413–423. 2009. View Article : Google Scholar
52	Sohn SI, Rim HK, Kim YH, et al: The ameliorative effect of 23-hydroxytormentic acid isolated from Rubus coreanus on cisplatin-induced nephrotoxicity in rats. Biol Pharm Bull. 34:1508–1513. 2011. View Article : Google Scholar : PubMed/NCBI
53	Wei Q, Dong G, Franklin J and Dong Z: The pathological role of Bax in cisplatin nephrotoxicity. Kidney Int. 72:53–62. 2007. View Article : Google Scholar : PubMed/NCBI
54	Yokoo T, Ohashi T, Shen JS, et al: Human mesenchymal stem cells in rodent whole-embryo culture are reprogrammed to contribute to kidney tissues. Proc Natl Acad Sci USA. 102:3296–3300. 2005. View Article : Google Scholar : PubMed/NCBI
55	Duffield JS and Bonventre JV: Kidney tubular epithelium is restored without replacement with bone marrow-derived cells during repair after ischemic injury. Kidney Int. 68:1956–1961. 2005. View Article : Google Scholar
56	Duffield JS, Park KM, Hsiao LL, et al: Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest. 115:1743–1755. 2005. View Article : Google Scholar : PubMed/NCBI