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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Kidney Injury / drug therapy
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Acute Kidney Injury / etiology
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Acute Kidney Injury / physiopathology
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Animals
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Cholesterol / blood
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Creatinine / blood
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Enzyme Inhibitors / administration & dosage
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Farnesyltranstransferase / antagonists & inhibitors
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Hyperlipidemias / complications
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Hyperlipidemias / drug therapy
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Kidney / blood supply*
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Kidney / drug effects
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Kidney / injuries*
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Kidney / physiopathology
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Male
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Methionine / administration & dosage
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Methionine / analogs & derivatives
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Mevalonic Acid / administration & dosage
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Mevalonic Acid / antagonists & inhibitors*
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Mevalonic Acid / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Pravastatin / administration & dosage
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Pravastatin / pharmacology*
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Reperfusion Injury / drug therapy*
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Reperfusion Injury / pathology
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Reperfusion Injury / physiopathology
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Reperfusion Injury / prevention & control
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Terpenes / metabolism
Substances
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Apolipoproteins E
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Enzyme Inhibitors
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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L 744832
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Terpenes
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Cholesterol
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Methionine
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Creatinine
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Farnesyltranstransferase
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Pravastatin
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Mevalonic Acid