Abstract P187: The Salt Sensitivity of Human GRK4 Transgenic Mice Is Associated With Renal Oxidative Stress

Variants of hGRK4 gamma are associated with human essential hypertension. hGRK4gamma 142V transgenic mice are hypertensive without oxidative stress on normal salt intake. hGRK4 gamma 486V transgenic mice have salt-sensitive hypertension. Because renal oxidative stress is increased in some rodent models of salt-sensitive hypertension, we quantified the renal expression of reactive oxygen species related proteins in hGRK4 gamma 486V transgenic mice and non-transgenic (NT) littermates, on normal (NS, 0 . 8% ) and high (HS, 4%) NaCl diets . Systolic blood pressure (measured under anesthesia) was similar in hGRK4 gamma 486V (89.83±2.7, mm Hg, n=9) and NT (94.7±2.5) mice on NS diet and elevated in hGRK4 gamma 486V (114±6.1) but not in NT mice (94.1±2.8) on HS diet. The renal expressions of NOX1, 2, and 4 were similar in both strains on NS diet but NOX2 was decreased by HS in NT (28±7, % of NT on NS diet, n=5-6/group). On NS diet, CuZnSOD and ECSOD were similar in the two mouse strains while MnSOD (66±3%) was lower in GRK4 gamma 486V than NT mice. However, on HS diet, CuZnSOD (87±7%), MnSOD (70±3%), and ECSOD (55±7%) were decreased in GRK4 gamma 486V mice but not altered in NT mice. HO-2, not HO-1, was slightly greater in GRK4 gamma 486V than NT mice on NS diet (117±7%) but this difference was abolished by HS diet. Urinary 8-isoprostane was lower in GRK4 gamma 486V than NT mice (57±2.5 vs 70±0.1, ng/mg of Cr) on NS diet but increased to a greater extent in GRK4 gamma 486V than NT mice (197±18 vs128±6) on HS diet. Renal SOD activity and superoxide production were similar in both mouse strains on NS diet. HS diet decreased SOD activity (81.6±2.7%) and increased superoxide (138.9±6.6%) production in GRK4 gamma 486V mice but not in NT mice. The renal tubular immunofluorescence of ECSOD was reduced to a greater extent in hGRK4 gamma 486V than NT by HS diet. HS diet also decreased the renal expression of NOS3, not NOS 1 and 2, in GRK4 gamma 486V mice (49±2%) but not in NT mice. These changes were not observed in the mice with hGRK4 gamma wildtype and hGRK4 gamma 142V transgenic mice, suggesting that the salt-sensitive hypertension of GRK4 gamma 486V mice is related to renal oxidative stress.