Protective effect of 17β-estradiol on ischemic acute renal failure through the PI3K/Akt/eNOS pathway

Estrogens attenuate renal injury induced by ischemia/reperfusion (I/R), an effect that is related to nitric oxide production in the post-ischemic kidney. The compound 17β-estradiol (E2-β) acting via estrogen receptors (ERs) is known to activate endothelial nitric oxide synthase (eNOS) through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. We determined if this pathway contributes to the renoprotective effect of E2-β in the uninephrectomized ischemia reperfusion rat model of acute renal injury. Treatment with E2-β suppressed the I/R-induced increases in blood urea nitrogen, plasma creatinine, urine flow, and fractional excretion of sodium while augmenting creatinine clearance, renal blood flow, and urine osmolality, indicating attenuation of renal injury. Phosphorylation of Akt and eNOS protein was significantly increased 30–60 min after reperfusion in estradiol-treated compared to vehicle-treated rats. The protective effects of E2-β and protein phosphorylation were reversed by the PI3K inhibitor wortmannin or the ER antagonist tamoxifen. Furthermore, the E2-β-induced renoprotective effects were not seen in eNOS knockout mice with renal injury. We conclude that the E2-β-induced renoprotective effect is due to activation of the PI3K/Akt pathway followed by increased eNOS phosphorylation in the post-ischemic kidney