Increased Renal Oxidative Stress in hGRK4 486V Transgenic Mice

Abstract

Variants of hGRK4 are associated with human essential hypertension. hGRK4486V transgenic mice have salt-sensitive hypertension. Because renal oxidative stress is increased in some rodent models of salt-sensitive hypertension, we quantified renal expression of reactive oxygen species-related proteins of hGRK4486V transgenic and non-transgenic (NT) mice on normal (NS, 0.8%) and high (HS, 4%) NaCl diets. Systolic blood pressure was similar in hGRK4486V (89.83±2.7, mm Hg, n=9) and NT (94.7±2.5) mice on NS diet and elevated in hGRK4486V (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 GRK4486V than NT mice. However, on HS diet, CuZnSOD (87±7%), MnSOD (70±3%), and ECSOD (55±7%) were decreased in GRK4486V mice not in NT mice. HO-2, not HO-1, was slightly greater in GRK4486V than NT mice on NS diet (117±7%) but this difference was abolished by HS diet. Urinary 8-isoprostane was lower in GRK4486V than NT mice (57±2.5 vs 70±0.1, ng/mg of Cr) on NS diet but increased to a greater extent in GRK4486V than NT mice (197±18 vs128±6) on HS diet. Renal SOD activity and superoxide production were similar in both strains on NS diet. HS diet decreased SOD activity (81.6±2.7%) and increased superoxide (138.9±6.6%) production in GRK4486V but not in NT mice. HS diet also decreased the renal expression of NOS3, not NOS 1 and 2, in GRK4486V (49±2%) but not in NT mice. These findings suggest that the salt-sensitive hypertension of GRK4486V mice is related to renal oxidative stress due to decreased protein expression and activity of SODs and decreased NOS3 protein.