Estrogen Receptor GPR30 Reduces Oxidative Stress and Proteinuria in the Salt-Sensitive Female mRen2.Lewis Rat

The current study assessed whether activation of the novel estrogen receptor GPR30 ameliorates salt-dependent renal damage in intact mRen2.Lewis (mRen2) females. Hemizygous mRen2 rats were maintained on either a normal salt (0.5% Na) or high-salt (HS; 4.0% Na) diet for 10 weeks (5 to 15 weeks of age), and HS animals were treated with the GPR30 agonist G-1 or vehicle for 2 weeks. Systolic blood pressure markedly increased with HS diet (149 +/- 3 to 219 +/- 5 mm Hg; P<0.01), but G-1 did not influence pressure (P=0.42). G-1 and estradiol induced relaxation of preconstricted mesenteric vessels from normal salt mRen2 rats, but both responses were attenuated in the HS group. Despite the lack of an effect on blood pressure, G-1 decreased renal hypertrophy, proteinuria, urinary 8-isoprostane excretion, and tubular 4-hydroxynonenal staining. HS diet significantly increased GPR30 mRNA (1.01 +/- 0.04 versus 1.59 +/- 0.13; P<0.01) and protein (0.60 +/- 0.31 versus 3.99 +/- 0.75; P<0.01) in the renal cortex. GPR30 was highly expressed in the brush border of proximal tubules and colocalized with megalin. Finally, megalin expression was reduced by HS diet and restored with G-1. We conclude that GPR30-mediated beneficial effects in salt-sensitive mRen2 females occurred independent of changes in systolic blood pressure. The failure of G-1 to influence pressure may reflect a salt-induced impairment in GPR30-mediated vasorelaxation. The renoprotective actions of GPR30 may involve attenuation of tubular oxidative stress and activation of megalin-mediated protein reabsorption. (Hypertension. 2011; 58:665-671.)