Abstract P607: Deletion of GPER Protects from Age-related Renovascular Dysfunction and Tubulo-interstitial Injury

Abstract

Aging is associated with reduced vasodilatory capacity in renal arteries. Activation of the G protein-coupled estrogen receptor (GPER) induces vasodilation and improves hypertensive renal injury in rats. Moreover, GPER, as observed with many G protein-coupled receptors, likely exhibits “basal activity” independent of ovarian estrogen production, which may become relevant in disease-like states such as aging. We hypothesized that deletion of basal GPER activity would further aggravate vasodilatory dysfunction in renal arteries and the associated tubulo-interstitial injury. In young (4 month-old) and senescent (24 month-old) male wild-type and GPER-deficient ( Gper -/- ) mice, blood pressure and endothelium-dependent vasodilation to acetylcholine in renal arteries were determined. In addition, vascular injury (VIS score) and tubulo-interstitial injury (TIS score) including staining for amyloid were quantified in histologic sections. In wild-type mice, aging markedly reduced renal artery vasodilation to acetylcholine (from 77±5% to 28±4% of precontraction, n=4-5, p<0.001 vs. young mice), and increased vascular injury (VIS: 0.42±0.07 vs. 0.04±0.03), tubulo-interstitial injury (TIS: 2.9±0.6 vs. 0.3±0.1), and amyloid staining (2.8±0.7 vs. 0±0, all n=6-8, p<0.001 vs. young mice). Contrary to our hypothesis, vasodilatory responses to acetylcholine were largely preserved in renal arteries from senescent Gper -/- mice (63±4 vs. 28±4% of precontraction, n=4-5, p<0.001 vs. wild-type mice). Similarly, in senescent Gper -/- mice, vascular injury (VIS) was reduced by 46% (n=6-7, p=0.09 vs. wild-type mice), as were tubulo-interstitial injury (TIS) and amyloid staining by 77% and 92%, respectively (both n=6-7, p<0.01 vs. wild-type mice). Deletion of Gper had no effect on blood pressure in either senescent (110±5/83±1 vs. 114±2/87±2 mmHg) or young animals (117±2/90±1 vs. 119±2/91±2 mmHg, both n=5-12, p=n.s. vs. wild-type mice). These results indicate a novel role for GPER expression in age-related impaired vasodilatory capacity in renal arteries and the associated tubulo-interstitial injury independent of blood pressure, as well as a pathophysiologically relevant activity of GPER in male mice, possibly independent of estrogen.