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

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.

Statin Use Associates with a Lower Incidence of Acute Kidney Injury after Major Elective Surgery

“…12,13 Studies using animal models have shown that giving statins before an ischemic event significantly reduces AKI. [8][9][10][11][12][13][14] Whether a similar benefit occurs in humans is uncertain. Some observational studies have shown that statins are associated with less AKI, whereas others have not.…”

Amelioration of Renal Ischemia–Reperfusion Injury by Inhibition of IL-6 Production in the Poloxamer 407–Induced Mouse Model of Hyperlipidemia

“…Campos et al (11) showed that kidney dysfunction after renal I /R tended to be less severe in rats fed a cholesterol-supplemented diet for 3 weeks before the insult than in control rats fed a regular diet over that period. Recently, we observed that although serum creatinine concentration after renal I/R did not differ between ApoE−/− and control mice, I/ R injury judged by histopathological analysis was less severe in the ApoE−/− animals (12). These data indicate that hyperlipidemia does not worsen but rather somewhat improves renal I /R injury.…”

Lipids, blood pressure and kidney update 2014

“…Statins administration might reduce oxidative stress, improve endothelial function and decrease inflammation [140,141]. Moreover, in experimental models of ischemiareperfusion, short-term statin treatment decreases renal dysfunction and inflammation [142,143]. Based on these data, the authors administrated high dose atorvastatin a day before surgery and continued until hospital discharge in statin naive patients; in those using statins prior to the study, treatment was administered until the day after surgery (https://www.asn-online.org/education/kidneyweek/ 2015/KW15_Late-Breakers.pdf ).…”