The induction of heat shock protein-72 attenuates cisplatin-induced acute renal failure in rats
- 87 Downloads
Induction of heat shock proteins (HSPs) is thought to play a protective role in ischaemic acute renal failure (ARF). However the role of HSPs in nephrotoxic ARF is not well explored. The aim of this study was to clarify the effects of the induction of HSP70s on cisplatin (CDDP) (6 mg/kg i.v.)-induced ARF in rats. Uranyl acetate (UA) or sodium arsenite (SA) were administered i.v. 14 days or 1 day respectively before CDDP injection to induce HSPs. Serum creatinine (SCr), tubular damage score and the numbers of apoptotic (TUNEL-positive) cells were examined 5 days after CDDP injection. The expression of HSP72, B-cell lymphoma gene product-2 (Bcl-2) and Bax were evaluated by Western blot analysis. We also investigated the effect of co-administration of chelerythrine chloride (Chel), which inhibits the induction of HSPs, with SA on the expression of HSP72 and nephrotoxicity. Pretreatment with UA or SA significantly induced renal HSP72 expression. Both UA and SA attenuated the CDDP-induced increase in SCr and tubular damage scores. Co-administration of Chel with SA abolished the SA-induced increment of HSP72 and the beneficial effects of SA. The protective effects of the induction of HSP72 were associated with an increased renal Bcl-2/Bax ratio and the reduction of TUNEL-positive cells in the outer stripe of outer medulla. Our findings suggest that HSP72 attenuates CDDP-induced nephrotoxicity. The protective effects of HSP72 are associated with an increased Bcl-2/Bax ratio and less apoptosis.
KeywordsCisplatin Acute renal failure HSP72 Apoptosis Bcl-2/Bax ratio Sodium arsenite Chelerythrine chloride
We are grateful to the Nippon Kayaku (Tokyo, Japan) for kindly providing CDDP. Part of this work was presented at the World Congress of Nephrology (San Francisco, October 17-20, 2001). This work was supported by a research grant sponsored by the Ministry of Education, Science, Sports and Culture of Japan.
- 3.Beck FX, Neuhofer W, Müller E (2000) Molecular chaperones in the kidney: distribution, putative roles, and regulation. Am J Physiol 279:F203–F215Google Scholar
- 21.Meldrum KK, Meldrum DR, Sezen SF, Crone JK, Burnett AL (2001) Heat shock prevents simulated ischemia-induced apoptosis in renal tubular cells via a PKC-dependent mechanism. Am J Physiol 281:R359–R364Google Scholar
- 32.Satoh K, Wakui H, Komatsuda A, Nakamoto Y, Miura AB, Itoh H, Tashima Y (1994) Induction and altered localization of 90-kDa heat-shock protein in rat kidneys with cisplatin-induced acute renal failure. Renal Fail 16:313–323Google Scholar
- 46.Zhou H, Miyaji T, Kato A, Fujigaki Y, Sano K, Hishida A (1999) The attenuation of cisplatin-induced acute renal failure is associated with the less apoptotic cell death. J Lab Clin Med 34:649–658Google Scholar
- 47.Zhou H, Kato A, Miyaji T, Fujigaki Y, Sano K, Hishida A (2000) Glycine attenuates apoptotic cell death in uranyl acetate-induced acute renal failure in rats. Clin Exp Nephrol 4:24–28Google Scholar