Renal insufficiency induced by cisplatin in rats is ameliorated by cyclosporin A.
Cyclosporin A (CsA) is a potent inhibitor of the Ca(2+)-dependent "pore" in isolated mitochondrial from diverse sources. Cisplatin-induced acute renal failure has been associated with morphological and functional alterations in renal cortex mitochondrial (RCM). This study was undertaken to examine the probable involvement of Ca(2+)-dependent permeabilization of RCM in cisplatin nephrotoxicity. RCM from rats injected with cisplatin (5 mg/kg body wt) 4 days earlier showed a significantly reduced capacity of retaining matrix Ca2+ and membrane potential in the presence of 15 nmol Ca2+/mg protein and 0.1 mM Pi (inorganic phosphate), compared to controls (those of rats that received carrier alone). These indices of mitochondrial dysfunction were restored to control levels when 1 microM CsA was added to assay media of RCM obtained from cisplatin-treated rats. Renal insufficiency induced by cisplatin assessed by serum creatinine and urea levels was significantly alleviated in rats 4 days after i.p. injections of cisplatin (5 mg/kg body wt) and CsA (50 micrograms/kg body wt), compared to those injected with cisplatin alone. Our findings support an involvement of Ca(2+)-mediated RCM damage in the mechanism of cisplatin nephrotoxicity, and suggest that suitable antagonists of Ca(2+)-dependent "pore" formation may improve renal tolerance to cisplatin.
Campbell
P I
PI
Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi-Arabia.
al-Nasser
I A
IA
D058186:Acute Kidney Injury / Q000139:chemically induced; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000097:blood
D000970:Antineoplastic Agents; D003524:Cyclosporins; D007166:Immunosuppressive Agents; C100000:cyclosporin C; D014508:Urea; D003404:Creatinine; D002945:Cisplatin; D002118:Calcium