Cisplatin, Cis-diamminedichloroplatinum (CDDP), is a platinum-based chemotherapy drug, and its chemotherapeutic use is restricted by nephrotoxicity. Inflammatory and apoptotic mechanisms play a central role in the pathogenesis of CDDP-induced acute kidney injury (AKI). The aim of this study was to compare the therapeutic potential of candesartan, angiotensin II receptor blocker, versus bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of CDDP-induced nephrotoxicity. Adult male Wistar rats (n = 40) were divided into four groups; Normal control: received saline injection, CDPP group: received CDDP injection (6 mg/kg single dose), Candesartan group: received candesartan (10 mg/kg/day) for 10 days + CDDP at day 3, and Stem cells group: received CDDP + BM-MSCs intravenously one day after CDDP injection. The rats were sacrificed seven days after CDDP injection. Significant elevation in serum creatinine and urea, renal levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1, renal expressions of nuclear factor kappa B (NF-κB), p38-mitogen-activated protein kinase (MAPK), caspase-3 and Bcl-2-associated x protein (Bax) were found in CDDP-injected rats when compared to normal rats. Both candesartan and BM-MSCs ameliorated renal function and reduced significantly the inflammatory markers (TNF-α , NF-κB, p38-MAPK and MCP-1) and apoptotic markers (caspase-3 and Bax) in renal tissue after CDDP injection. Candesartan as well as BM-MSCs have anti-inflammatory and anti-apoptotic actions and they can be used as nephroprotective agents against CDDP-induced nephrotoxicity. BM-MSCs is more effective than candesartan in amelioration of AKI induced by CDDP.
MillerRPTadagavadiRKRameshGReevesWB. Mechanisms of cisplatin nephrotoxicity. Toxins2010; 2: 2490–518.
2.
YaoXPanichpisalKKurtzmanNNugentK. Cisplatin nephrotoxicity: a review. Am J Med Sci2007; 334: 115–24.
3.
KaplanN. Angiotensin II-receptor blockers: will they replace angiotensin-converting enzyme inhibitors in the treatment of hypertension?J Human Hypertens2000; 14: S87–90.
4.
IbrahimMAAshourOMIbrahimYFEl-BitarHIGomaaWAbdel-RahimSR. Angiotensin-converting enzyme inhibition and angiotensin-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res2009; 60: 373–81.
5.
YamagishiSTakeuchiM. Telmisartan is a promising cardiometabolic sartan due to its unique PPAR-γ-inducing property. Med Hypotheses2005; 64: 476–8.
6.
AzizMTAWassefMAAAhmedHHRashedLMahfouzSAlyMIHusseinREAbdelazizM. The role of bone marrow derived-mesenchymal stem cells in attenuation of kidney function in rats with diabetic nephropathy. Diab Metab Syndr2014; 6: 34.
7.
EliopoulosNZhaoJBouchentoufMFornerKBirmanEYuanSBoivinMNMartineauD. Human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection. Am J Physiol-Renal Physiol2010; 299: F1288–98.
8.
MorigiMIntronaMImbertiBCornaDAbbateMRotaCRottoliDBenigniAPericoNZojaCRambaldiARemuzziARemuzziG. Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cell2008; 26: 2075–82.
9.
ChengKRaiPPlagovALanXKumarDSalhanDRehmanSMalhotraABhargavaKPalestroCJGuptaSSinghalPC. Transplantation of bone marrow-derived MSCs improves cisplatinum-induced renal injury through paracrine mechanisms. Experiment Mol Pathol2013; 94: 466–73.
10.
LennonDPCaplanAI. Isolation of rat marrow-derived mesenchymal stem cells. Exp Hematol2006; 34: 1606–7.
11.
McLimansWFDavisEVGloverFLRakeGW. The submerged culture of mammalian cells: the spinner culture. J Immunol1957; 79: 428–33.
12.
HelmyMHelmyMALLAHDZAIDAEL-DINMM. Role of nitergic and endothelin pathways modulations in cisplatin-induced nephrotoxicity in male rats. JPP2014; 3: 08.
13.
AshrafiFNematbakhshMSafariTTalebiANasriHKhazaeiMBaradaran-MahdaviMMJafapishehAOliaBPirhajiOHashemi-NiaSJEshraghiFPezeshkiZMortazaviM. A combination of vitamin C and losartan for cisplatin-induced nephrotoxicity in rats. Iranian J Kidney Dis2012; 6: 361–5.
14.
SalehSAin-ShokaAAEl-DemerdashEKhalefMM. Protective effects of the angiotensin II receptor blocker losartan on cisplatin-induced kidney injury. Chemotherapy2009; 55: 399–406.
15.
LiuNTianJChengJZhangJ. Effect of erythropoietin on the migration of bone marrow-derived mesenchymal stem cells to the acute kidney injury microenvironment. Experiment Cell Res2013; 319: 2019–27.
16.
LivakKJSchmittgenTD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods2001; 25: 402–8.
17.
El-GarhyAMEl-RaoufAOlaMEl-SayehBMFawzyHMAbdallahDM. Ellagic acid antiinflammatory and antiapoptotic potential mediate renoprotection in cisplatin nephrotoxic rats. J Biochem Mol Toxicol2014; 28: 472–9. .
İş eriSErcanFGedikNYükselMAlicanİ. Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology2007; 230: 256–64.
20.
UekiMUenoMMorishitaJMaekawaN. D-ribose ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice. Tohoku J Experiment Med2013; 229: 195–201.
21.
BoyleJJWeissbergPLBennettMR. Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms. Arterioscler Thromb Vasc Biol2003; 23: 1553–8.
22.
BanasBLuckowBMÖLLERMKlierCNelsonPJSchaddeEBriglMHalevyDHolthöferHReinhartBSchlöndorffD. Chemokine and chemokine receptor expression in a novel human mesangial cell line. J Am Soc Nephrol1999; 10: 2314–22.
23.
SongJLiuDFengLZhangZJiaXXiaoW. Protective effect of standardized extract of Ginkgo biloba against cisplatin-induced nephrotoxicity. Evid-Based Complement Alternat Med2013, pp. 2013.
24.
JiangMDongZ. Regulation and pathological role of p53 in cisplatin nephrotoxicity. J Pharmacol Experiment Therapeut2008; 327: 300–7.
25.
AdamsJLBadgerAMKumarSLeeJC. p38 MAP kinase: molecular target for the inhibition of pro-inflammatory cytokines. Progr Med Chem2001; 38: 1–60.
26.
RashedLAHashemRMSolimanHM. Oxytocin inhibits NADPH oxidase and P38 MAPK in cisplatin-induced nephrotoxicity. Biomed Pharmacother2011; 65: 474–80.
27.
QiSWuD. Bone marrow-derived mesenchymal stem cells protect against cisplatin-induced acute kidney injury in rats by inhibiting cell apoptosis. Int J Mol Med2013; 32: 1262–72.
28.
OrtizALorzCCatalánMPDanoffTMYamasakiYEgidoJNeilsonEG. Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure. Kidney Int2000; 57: 969–81.
BorregoAZamoraZBGonzálezRRomayCMenéndezSHernándezFBerlangaJMonteroT. Ozone/oxygen mixture modifies the subcellular redistribution of Bax protein in renal tissue from rats treated with cisplatin. Archive Med Res2006; 37: 717–22.
31.
JiangMWeiQWangJDuQYuJZhangLDongZ. Regulation of PUMA-α by p53 in cisplatin-induced renal cell apoptosis. Oncogene2006; 25: 4056–66.
32.
RastghalamRNematbakhshMBahadoraniMEshraghi-JaziFTalebiAMoeiniMAshrafiFShirdavaniS. Angiotensin Type-1 receptor blockade may not protect kidney against cisplatin-induced nephrotoxicity in rats. ISRN Nephrology2014; 2014: 479645.
33.
LiuPFengYDongCYangDLiBChenXZhangZWangYZhouYZhaoL. Administration of BMSCs with muscone in rats with gentamicin-induced AKI improves their therapeutic efficacy. PloS ONE2014; 9: e97123.
34.
YuCGongRRifaiATolbertEMDworkinLD. Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection. J Am Soc Nephrol2007; 18: 750–9.
35.
ChenSGeYSiJRifaiADworkinLDGongR. Candesartan suppresses chronic renal inflammation by a novel antioxidant action independent of AT1R blockade. Kidney Int2008; 74: 1128–38.
36.
LvJJiaRYangDZhuJDingG. Candesartan attenuates Angiotensin II-induced mesangial cell apoptosis via TLR4/MyD88 pathway. Biochem Biophys Res Commun2009; 380: 81–6.
