Pravastatin improves renal ischemia-reperfusion injury by inhibiting the mevalonate pathway.
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.
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
Satoru
S
Sharyo
Naoko
N
Yokota-Ikeda
Miyuki
M
Mori
Kazuyoshi
K
Kumagai
Kazuyuki
K
Uchida
Katsuaki
K
Ito
Melissa J
MJ
Burne-Taney
Hamid
H
Rabb
Masahiro
M
Ikeda
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D003404:Creatinine / Q000097:blood; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives; D008798:Mevalonic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D013729:Terpenes / Q000378:metabolism
D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096898:L 744832; D013729:Terpenes; D002784:Cholesterol; D008715:Methionine; D003404:Creatinine; D051231:Farnesyltranstransferase; D017035:Pravastatin; D008798:Mevalonic Acid