Knockout of g-adducin promotes N^G-nitro-L-arginine-methyl-ester–induced hypertensive renal injury

Previous studies identified a region on chromosome 1 associated with N^G-nitro-L-arginine methyl ester (L-NAME) hypertension-induced renal disease in fawn-hooded hypertensive (FHH) rats. This region contains a mutant g-adducin (Add3) gene that impairs renal blood flow (RBF) autoregulation, but its contribution to renal injury is unknown. The present study evaluated the hypothesis that knockout (KO) of Add3 impairs the renal vasoconstrictor response to the blockade of nitric oxide synthase and enhances hypertension-induced renal injury after chronic administration of L-NAME plus a high-salt diet. The acute hemodynamic effect of L-NAME and its chronic effects on hypertension and renal injury were compared in FHH 1^{Brown Norway} (FHH 1^BN) congenic rats (WT) expressing wild-type Add3 gene versus FHH 1^BN Add3 KO rats. RBF was well autoregulated in WT rats but impaired in Add3 KO rats. Acute administration of L-NAME (10 mg/kg) raised mean arterial pressure (MAP) similarly in both strains, but RBF and glomerular filtration rate (GFR) fell by 38% in WT versus 15% in Add3 KO rats. MAP increased similarly in both strains after chronic administration of L-NAME and a high-salt diet; however, proteinuria and renal injury were greater in Add3 KO rats than in WT rats. Surprisingly, RBF, GFR, and glomerular capillary pressure were 41%, 82%, and 13% higher in L-NAME–treated Add3 KO rats than in WT rats. Hypertensive Add3 KO rats exhibited greater loss of podocytes and glomerular nephrin expression and increased interstitial fibrosis than in WT rats. These findings indicate that loss of ADD3 promotes L-NAME–induced renal injury by altering renal hemodynamics and enhancing the transmission of pressure to glomeruli. SIGNIFICANCE STATEMENT A mutation in the g-adducin (Add3) gene in fawn-hooded hypertensive rats that impairs autoregulation of renal blood flow is in a region of rat chromosome 1 homologous to a locus on human chromosome 10 associated with diabetic nephropathy. The present results indicate that loss of ADD3 enhanced N^G-nitro-Larginine methyl ester–induced hypertensive renal injury by altering the transmission of pressure to the glomerulus.