Pravastatin attenuates carboplatin-induced nephrotoxicity in rodents via peroxisome proliferator-activated receptor α-regulated heme oxygenase-1

Hsi Hsien Chen, Tzen Wen Chen, Heng Lin

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Abstract

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 F1α, enhanced nuclear translocation of peroxisome proliferator-activated receptor-α (PPARα), and increased HO-1 promoter and peroxisome proliferator response element (PPRE) activities. We found interaction of PPARα 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 PPARα and HO-1 in wild-type mice, and HO-1 expression was significantly attenuated in PPARα-knockout mice. These results indicate that pravastatin up-regulates HO-1 and protects against carboplatin-induced renal dysfunction and apoptosis via a PPARα-dependent pathway.

Original languageEnglish
Pages (from-to)36-45
Number of pages10
JournalMolecular Pharmacology
Volume78
Issue number1
DOIs
Publication statusPublished - Jul 2010

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ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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