Induction of Apelin by Losartan in Renal Ischemia/Reperfusion Injury in Rats - Implication of Endothelial Nitric Oxide Synthase (Enos) Phosphorylation

Abstract

Apelin and its G-protein-coupled receptor APJ system and renin-angiotensin system have opposing actions on ischemia/reperfusion (I/R) injury. However, changes in renal apelin content after administration of losartan, an angiotensin-II receptor blocker (ARB), in renal I/R injury rat model has not been elucidated. Male Wistat rats were pretreated for 14 days with losartan; losartan+L-NAME, non-selective endothelial nitric oxide synthase (eNOS) inhibitor; or saline, then subjected to bilateral renal artery occlusion for 40 min followed by 2h (early) or 24h (late) of reperfusion (n=10 rats/group at each time point). I/R injury resulted in suppression of renal apelin content, and phosphorylated eNOS (P-eNOS) expression, that were more aggravated after 24h compared to 2h of reperfusion. Losartan pretreatment significantly ameliorated renal insult (as shown by decreased blood urea, serum creatinine, renal malondialdehyde, caspase-3 expression and histopathological scoring), which was concomitant with up regulation of renal tissue apelin levels and P-eNOS expression. Co-administration of L-NAME with losartan completely cancelled its renoprotective effect after 2h of reperfusion. However, some protection was reserved in late reperfusion rats. These findings suggest that the protection offered by losartan against early and late renal I/R injury is associated with induction of renal apelin content and eNOS phosphorylation.