Altered Functioning of Both Renal Dopamine D1 and Angiotensin II Type 1 Receptors Causes Hypertension in Old Rats

Abstract

Activation of renal dopamine D1 (D1R) and angiotensin II type 1 receptors (AT(1)Rs) influences the activity of proximal tubular sodium transporter Na,K-ATPase and maintains sodium homeostasis and blood pressure. We reported recently that diminished D1R and exaggerated AT(1)R functions are associated with hypertension in old Fischer 344 × Brown Norway F1 (FBN) rats, and oxidative stress plays a central role in this phenomenon. Here we studied the mechanisms of age-associated increase in oxidative stress on diminished D1R and exaggerated AT(1)R functions in the renal proximal tubules of control and antioxidant Tempol-treated adult and old FBN rats. Although D1R numbers and D1R agonist SKF38393-mediated stimulation of [(35)S]-GTPγS binding (index of D1R activation) were lower, G protein-coupled receptor kinase 4 (kinase that uncouples D1R) levels were higher in old FBN rats. Tempol treatment restored D1R numbers and G protein coupling and reduced G protein-coupled receptor kinase 4 levels in old FBN rats. Angiotensin II-mediated stimulation of [(35)S]-GTPγS binding and Na,K-ATPase activity were higher in old FBN rats, which were also restored with Tempol treatment. We also measured renal AT(1)R function in adult and old Fischer 344 (F344) rats, which, despite exhibiting an age-related increase in oxidative stress and diminished renal D1R function, are normotensive. We found that diuretic and natriuretic responses to candesartan (indices of AT(1)R function) were similar in F344 rats, a likely explanation for the absence of age-associated hypertension in these rats. Perhaps, alterations in both D1R (diminished) and AT(1)R (exaggerated) functions are necessary for the development of age-associated hypertension, as seen in old FBN rats.