Role of Angiotensin II Type 2 Receptors in Oxidative Stress and Inflammation

Sodium imbalance, inflammation and oxidative stress are believed to contribute to hypertension in obesity/diabetes. The renin angiotensin system (RAS) is the major hormonal system which affects sodium balance, oxidative stress and inflammation mainly via activation of Angiotensin II- AT1 receptors. We have recently shown that renal AT2 receptors are upreguated in obese animal and contribute to natriuresis. However, the role of AT2 receptors in oxidative stress and inflammation is not well studied. On the other hand, oxidative stress can positively influence sodium retention independently. However the existence of possible cross-talk between oxidative stress, in particular superoxide radicals, and RAS system in terms of renal sodium handling is not known. In order to determine the possible interaction between RAS system and oxidative stress in terms of sodium homeostasis and role of AT2 receptors in oxidative stress and inflammation, we designed acute and chronic studies.

The acute study was designed to investigate the role of NAD(P)H oxidase (NOX), a major superoxide radical producing enzyme, in AT1 and AT2 receptor function on natriuresis/diuresis in Sprague-Dawley (SD), lean Zucker and obese Zucker rats. The results suggested that NAD(P)H oxidase has its independent role in natriuresis. Inhibition of NAD(P)H oxidase had no effect in AT1 receptor antagonist (candesartan) induced natriuresis in SD and lean Zucker rats suggesting there is no interaction between AT1 receptor and oxidative stress in terms of natriuresis in SD or lean rats. On the other hand inhibition of NAD(P)H oxidase tremendously increased AT2 receptor agonist (CGP-42112A)-mediated natriuresis by increasing the NO/cGMP availability; suggesting that NAD(P)H oxidase can obstruct AT2 receptor function in SD rats. In obese Zucker rats inhibition of NAD(P)H oxidase unexpectedly prevented candesartan induced natriuresis by unknown mechanism.

Secondly, we looked into the effect of chronic activation of AT2 receptors in oxidative stress and inflammation. Lean and obese Zucker rats were treated with AT2 receptor agonist CGP-42112A for 2-weeks and at the end of treatment period level of oxidative stress markers and inflammatory markers/mediators were measured. The results suggested that chronic AT2 receptor activation can reduce oxidative stress and inflammation in obese Zucker rats. AT2 receptor activation decreased hemeoxygenase-1 (HO-1) and gp-91phox expression, increased superoxide dismutase (SOD) activity, decreased TNF-α, IL-1β, IL-6, C-reactive protein (CRP) and monocytes chemoattractant protein -1(MCP-1) levels in obese Zucker rats. On the contrary, chronic AT2 receptor activation may lead to increase oxidative stress (increased gp-91phox) and inflammation (increased TNF-α and IL-1β) in lean rats.

Overall the studies demonstrate that superoxides can obstruct AT2 receptor function during physiological condition. However chronic activation of AT2 receptor can have anti-inflammatory and anti-oxidative function in obese Zucker rats but pro-inflammatory and pro-oxidative function in lean Zucker rats.