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 were maintained on either a normal salt (NS, 0.5% Na) or high salt (HS, 4% Na) diet for 10 wks (5 to 15 wks of age), and HS animals were treated with the GPR30 agonist G-1 or vehicle for two weeks. Systolic blood pressure markedly increased with HS [149 ± 3 to 219 ± 5 mmHg, P<0.01], but G-1 did not influence pressure [P=0.42]. G-1 and estradiol induced relaxation of pre-constricted mesenteric vessels from NS mRen2, 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-HNE staining. HS significantly increased GPR30 mRNA [1.01 ± 0.04 vs. 1.59 ± 0.13; P<0.01] and protein [0.60 ± 0.31 vs. 3.99 ± 0.75; P<0.01] in the renal cortex. GPR30 was highly expressed in the brush border of proximal tubules and co-localized with megalin. Finally, megalin expression was reduced by HS 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.