Pituitary Adenylate Cyclase-Activating Polypeptide Prevents Cisplatin-Induced Renal Failure
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Cisplatin is widely used for cancer chemotherapy, but nephrotoxicity is a major dose-limiting side effect. Our recent studies in vitro have shown that pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorated cisplatin nephrotoxicity and that the renoprotection with PACAP38 was mediated by the PAC1 receptor and through the p53-dependent and -independent suppression of apoptosis of human renal proximal tubular epithelial cells. In the present studies, PACAP38 prevented the rise in blood urea nitrogen and serum creatinine in mice treated with cisplatin. Cisplatin-exposed mice treated with PACAP38 had relatively well-preserved tubular integrity, even when the treatment started 24 h after cisplatin exposure. PACAP38 also reduced plasma and kidney levels of tumor necrosis factor-α and restored collagen IV levels. The damage to mouse kidney tubules caused by cisplatin involved p53 accumulation and was partially reversed by treatment with PACAP38. PACAP38 ameliorates cisplatin-induced acute kidney injury even when treatment started 24 h after the onset of injury and increases tubular regeneration, which further facilitates restoration of kidney function in addition to its anti-apoptotic effects.
KeywordsApoptosis Cancer chemotherapy Extracellular matrix Inflammation p53 Renoprotection
The authors thank Drs. Samir El-Dahr and Zubaida Saifudeen in the Pediatric Nephrology Section at the Tulane University School of Medicine for providing kidneys from p53−/− mice. We also thank Wei Cai and Kristine E. Gullo for assistance with immunoblots, RNA analyses, and bioassays.
This work was supported in part by the Research Commercialization and Educational Enhancement Program of the Louisiana Board of Regents (013RCEEP-07 to M.L., J.L.M. and V.B.), the Dialysis Clinic, Inc. (research endowment to V.B.), and the Arimura Foundation (research grant to M.L.).
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