ROLE OF AGE-ASSOCIATED OXIDATIVE STRESS IN ALTERED RENAL D1 AND AT1 RECEPTOR FUNCTIONS AND HYPERTENSION
Blood pressure (BP) and oxidative stress increase with aging. Renal dopamine D1 (D1R) and angiotensin AT1 (AT1R) receptors by maintaining sodium homeostasis regulate blood pressure. Impaired D1R and exaggerated AT1R functions in the kidneys contribute to hypertension in animal models, which also exhibit oxidative stress. However, the role of oxidative stress in age-related hypertension has not been studied. In this study, we hypothesized that age-associated increase in oxidative stress by altering renal D1R and AT1R functions cause high BP in aging.
To test this hypothesis, we measured oxidative stress, BP, and D1 and AT1 receptor functions in adult (3-month) and old (21-month) Fischer 344 X Brown Norway F1 (FBN) rats supplemented without/with antioxidant tempol. We found age-related increases in oxidative stress and blood pressure; which were reduced with tempol treatment in old FBN rats. D1R and AT1R functions were determined by measuring diuretic and natriuretic responses to SKF-38393 (D1R agonist) and candesartan (AT1 receptor antagonist) respectively. Natriuresis in response to D1R activation was impaired in old rats, suggesting an age-associated decline in D1R function in old FBN rats. Increase in G protein coupled receptor kinase (GRK) expression/activity is associated with reduced D1R-G protein coupling and function in humans and animal models with hypertension. We found age-associated increase in GRK-4 levels accompanied with D1R-G protein uncoupling in the renal proximal tubules of old FBN rats. Tempol treatment reduced GRK-4 levels and restored D1R-G protein coupling in these old rats. Natriuretic and diuretic responses to candesartan; however, were exaggerated in old rats, suggesting an age-associated increase in renal AT1R function in old FBN rats. Age-related increases in angiotensin II-mediated G protein coupling leading to exaggerated Na,K-ATPase activity may have caused increased renal AT1R function observed in old FBN rats. Tempol treatment restored angiotensin II-mediated G protein coupling and Na,K-ATPase response and thus reduced candesartan-mediated natriuresis and diuresis in old FBN rats. Our results demonstrate that both diminished renal D1R and exaggerated AT1R functions are associated with high BP in old FBN rats. Furthermore, oxidative stress may cause altered renal D1R and AT1R functions and high BP in these old rats.