Angiotensin type 1 receptor (AT1) double null mice (DKO) exhibit augmented renal renin and neuronal nitric oxide synthase (nNOS) protein expression

Abstract

DKO mice display reduced blood pressure, renal vascular thickening, medullary atrophy, and tubulointerstitial injury. Juxtamedullary efferent arterioles of AT1A−/− mice, and afferent arterioles of DKO mice exhibit significantly larger baseline vessel diameters compared to wild type (WT). We propose that an imbalance of AngII and nitric oxide signaling produces renal microvascular dilation. Kidneys were harvested from WT, AT1B−/−, AT1A−/−, and DKO mice, fixed, sectioned, and immunostained for renin and nNOS protein localization. The percent of glomeruli positive for JGA renin and the density of JGA renin immunostaining were significantly higher in AT1A−/− and DKO than WT (60±1%, n=3; 56±9%, n=6; 22±3%, n=6 and 15±9; 15±7; 1±0 fold, respectively). Renin expression of AT1B−/− was not different from WT. AT1A−/− and DKO mice displayed significant recruitment of renin protein expression along the afferent arteriole and interlobular artery (15±7%, 7±3 vessels/kidney n=3; 9±3%, 3±1 vessels/kidney n=6, respectively) compared to WT. WT and AT1B−/− kidneys displayed only JGA renin. Percent of glomeruli with positive MD nNOS immunostaining was not different for WT, AT1A−/−, AT1B−/− and DKO kidneys (46±2, 33±4, 34±, 38±5%), however, AT1A−/− kidneys demonstrated a significant increase in the percent of glomeruli with nNOS positive JGA (19±5 WT, 52±3 AT1A−/−, 8±3 AT1B−/−, 33±10 DKO), afferent arterioles, and interlobular arteries. Density of MD nNOS immunostaining was 7.0±2.6 fold in DKO compared to WT. Density of vascular nNOS immunostaining was 20±7 fold in AT1A−/− relative to WT. Loss of AT1 receptor signaling is coupled to enhanced nNOS protein expression in renal tubular and microvascular structures and may lead to increases in nitric oxide generation. NIDDK-62003 & P20RR018766