Activation of AT2 receptors reduces renal AT1 receptor function and enhances ACE2 activity in obese Zucker rats

Earlier, we reported that AT 2 R activation inhibits renal Na + K + ‐ ATPase (NKA), promotes natriuresis and in the long‐term regulates blood pressure (BP) in obese rats (OZR). In the present study, we investigated whether AT 2 R activation influences other components of the renin angiotensin system and thereby regulates renal function and BP in obesity. We treated OZR with AT 2 R agonist CGP (1 μg/kg/min, for 2‐wks). The CGP‐treatment caused decrease in BP, which was associated with reduction in Na‐balance, early increase in urinary nitrates and cGMP and no change in GFR compared to obese controls. Under anesthesia, pressor response to Ang II and candesartan‐induced natriuresis was reduced in CGP‐treated OZR compared to control OZR. In‐vitro study in the proximal tubules from OZR revealed that AT 2 R activation, via cGMP pathway reduced AT 1 R‐mediated NKA stimulation. While no changes was seen in renal expression of AT 1 R, AT 2 R or ACE, ACE2 expression/activity was 4‐fold increased and PRA was decreased in CGP‐treated as compared to control OZR. We conclude that activation of AT 2 R reduces AT 1 R function, PRA and increases ACE2/ACE, which collectively may have contributed to natriuresis and BP reduction. These findings highlight the importance of AT 2 R in reducing the anti‐natriuretic AT 1 R function and enhancing the protective ACE2 axis of RAS that could serve as a therapeutic target for treating obesity related hypertension. NIH RO1‐DK61578