Pravastatin improves renal ischemia-reperfusion injury by inhibiting the mevalonate pathway

Satoru Sharyo, Naoko Yokota-Ikeda, Miyuki Mori, Kazuyoshi Kumagai, Kazuyuki Uchida, Katsuaki Ito, Melissa J. Burne-Taney, Hamid Rabb, Masahiro Ikeda

Research output: Contribution to journalArticlepeer-review

Abstract

Statins are known to lessen the severity of renal ischemia-reperfusion injury. The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model. Treatment of mice with pravastatin, a widely used statin, improved renal function after renal ischemia-reperfusion without lowering the plasma cholesterol level. Administration of pravastatin with mevalonate, a product of HMG-CoA reductase, eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism. In hypercholestrolemic apolipoprotein E knockout mice with reduced HMG-CoA reductase activity; the degree of injury was less severe than in control mice, however, there was no protective action of pravastatin on renal injury in the knockout mice. Treatment with a farnesyltransferase inhibitor (L-744832) mimicked pravastatin's protective effect but co-administration with the statin provided no additional protection. Both pravastatin and L-744832 inhibited the injury-induced increase in plasma IL-6 concentration to a similar extent. Our results suggest the protective effect of pravastatin on renal ischemia-reperfusion injury is mediated by inhibition of the mevalonate-isoprenoid pathway independent of its lipid lowering action.

Original languageEnglish (US)
Pages (from-to)577-584
Number of pages8
JournalKidney international
Volume74
Issue number5
DOIs
StatePublished - Sep 2008

Keywords

  • Apolipoprotein E knockout mouse
  • Farnesyltransferase inhibitor
  • Ischemia-reperfusion injury
  • Pravastatin
  • The mevalonate pathway

ASJC Scopus subject areas

  • Nephrology

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