Pravastatin attenuates carboplatin-induced nephrotoxicity in rodents via peroxisome proliferator-activated receptor alpha-regulated heme oxygenase-1.
The aim of this study was to explore the molecular mechanisms underlying the protective effect of pravastatin against carboplatin-induced nephrotoxicity in rodents. We exposed rat NRK-52E renal tubular epithelial cells to carboplatin, with or without pravastatin. Pravastatin decreased production of reactive oxygen species, increased expression of heme oxygenase-1 (HO-1), cyclooxygenase-2, and 6-keto prostaglandin F1alpha, enhanced nuclear translocation of peroxisome proliferator-activated receptor-alpha (PPARalpha), and increased HO-1 promoter and peroxisome proliferator response element (PPRE) activities. We found interaction of PPARalpha with PPRE on the HO-1 promoter in nuclear extracts from pravastatin-treated NRK-52E cells and by chromatin immunoprecipitation. We pretreated mice with pravastatin and then administered a single intraperitoneal injection of carboplatin. Effects on renal function, morphology, apoptosis, and survival were assessed. In response to carboplatin injection, mice developed acute renal failure, with elevated activated caspase-3, increased apoptotic bodies, and decreased survival. Pretreatment with pravastatin significantly ameliorated renal dysfunction and apoptosis and improved renal morphology and survival. Injection of pravastatin also induced overexpression of PPARalpha and HO-1 in wild-type mice, and HO-1 expression was significantly attenuated in PPARalpha-knockout mice. These results indicate that pravastatin up-regulates HO-1 and protects against carboplatin-induced renal dysfunction and apoptosis via a PPARalpha-dependent pathway.
Chen
Hsi-Hsien
HH
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chen
Tzen-Wen
TW
Lin
Heng
H
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016190:Carboplatin / Q000009:adverse effects*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000502:physiology*; D017035:Pravastatin / Q000494:pharmacology*; D011401:Promoter Regions, Genetic
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047493:PPAR alpha; D016190:Carboplatin; D006419:Heme Oxygenase (Decyclizing); D017035:Pravastatin