Abstract-Angiotensin II type 2 receptor (AT 2 R) counteracts most effects of angiotensin II type 1 receptor (AT 1 R). We hypothesized that direct AT 2 R stimulation reduces renal production of the inflammatory cytokines tumor necrosis factor-␣ (TNF-␣), interleukin-6 (IL-6), and transforming growth factor-␤1 (TGF-␤1) and enhances the production of nitric oxide (NO) and cyclic guanosine 3Ј,5Ј-monophosphate (cGMP) in the clipped kidney of 2-kidney, 1-clip (2K1C) hypertension rat model. We used Sprague-Dawley rats to evaluate changes in renal interstitial fluid recovery levels of TNF-␣, IL-6, NO, and cGMP; renal expression of AT 1 R, AT 2 R, TGF-␤1, TNF-␣, and IL-6 in sham and 2K1C rats treated for 4 days with vehicle, AT 2 R agonist compound 21 (C21), or AT 2 R antagonist PD123319 (PD), alone and combined (nϭ6, each group). Systolic blood pressure increased significantly in 2K1C and was not influenced by any treatment. Clipped kidneys showed significant increases in renal expression of AT 1 R, AT 2 R, TNF-␣, IL-6, TGF-␤1 and decreases in NO and cGMP levels. These factors were not influenced by PD treatment. In contrast, C21 caused significant decrease in renal TNF-␣, IL-6, TGF-␤1 and an increase in NO and cGMP levels. Combined C21 and PD treatment partially reversed the observed C21 effects. Compared to sham, there were no significant changes in TNF-␣, IL-6, TGF-␤1, NO, or cGMP in the nonclipped kidneys of 2K1C animals. We conclude that direct AT 2 R stimulation reduces early renal inflammatory responses and improves production of NO and cGMP in renovascular hypertension independent of blood pressure reduction. (Hypertension. 2011;57:308-313.) • Online Data Supplement

SUMMARY (Pro)renin receptor (PRR) binding to renin or prorenin mediates Ang II dependent and independent effects. PRR expression was increased in the kidneys of diabetic rats but its role in diabetic nephropathy is unknown. We investigated the contribution of PRR to the development of diabetic nephropathy through enhancement of renal production of tumor necrosis factor-α (TNF-α) and interleukine-1β (IL-1β).Normoglicemic control and streptozotocin-induced diabetes Sprague-Dawley rats were studied. We evaluated urine albumin-to-creatinine ratio (UACR), renal interstitial fluid (RIF) levels of Ang II, TNF-α, and IL-1β, and the renal expression of TNF- α and IL-1β in control, non-treated diabetes, and diabetes treated with PRR blocker (PRRB), AT1 receptor blocker valsartan, or combined therapy, administered directly to the renal cortical interstitium for 14 days via osmotic minipump.Compared to normoglycemic control, UACR and RIF Ang II, TNF-α, and IL-1β were significantly higher in diabetic rats. PRRB or valsartan individually and combined significantly reduced UACR, RIF TNF-α and IL-1β levels. Renal expressions of TNF-α and IL-1β were higher in non-treated diabetic rats and significantly reduced by PRRB or valsartan individually and combined. Renal PRR expression was increased in non-treated and PRRB treated diabetic rats, and reduced in rats receiving valsartan alone or combined therapy. RIF Ang II was not influenced by PRRB, while valsartan alone and combined with PRRB significantly increased its levels.We conclude that PRR is involved in the development and progression of kidney disease in diabetes by enhancing renal production of inflammatory cytokines TNF-α and IL-1β, independently of renal Ang II effects.

Our recent studies have demonstrated that salt excess in the spontaneously hypertensive rat (SHR) produces a modestly increased arterial pressure while promoting marked myocardial fibrosis and structural damage associated with altered coronary hemodynamics and ventricular function. The present study was designed to determine the efficacy of an angiotensin II type 1 (AT 1) receptor blocker (ARB) in the prevention of pressure increase and development of target organ damage from high dietary salt intake. Eight-week-old SHRs were given an 8% salt diet for 8 wk; their ageand gender-matched controls received standard chow. Some of the salt-loaded rats were treated concomitantly with ARB (candesartan; 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). The ARB failed to reduce the salt-induced rise in pressure, whereas it significantly attenuated left ventricular (LV) remodeling (mass and wall thicknesses), myocardial fibrosis (hydroxyproline concentration and collagen volume fraction), and the development of LV diastolic dysfunction, as shown by longer isovolumic relaxation time, decreased ratio of peak velocity of early to late diastolic waves, and slower LV relaxation (minimum first derivative of pressure over time/maximal LV pressure). Without affecting the increased pulse pressure by high salt intake, the ARB prevented the salt-induced deterioration of coronary and renal hemodynamics but not the arterial stiffening or hypertrophy (pulse wave velocity and aortic mass index). Additionally, candesartan prevented the saltinduced increase in kidney mass index and proteinuria. In conclusion, the ARB given concomitantly with dietary salt excess ameliorated salt-related structural and functional cardiac and renal abnormalities in SHRs without reducing arterial pressure. These data clearly demonstrated that angiotensin II (via AT 1 receptors), at least in part, participated importantly in the pressure-independent effects of salt excess on target organ damage of hypertension. left ventricular function; fibrosis; coronary circulation; angiotensi II type 1 receptor blocker

Although angiotensin II subtype-2 receptor (AT2R) was discovered over two decades ago, its contribution to physiology and pathophysiology is not fully elucidated. Current knowledge suggests that under normal physiologic conditions, AT2R counterbalances the effects of angiotensin II subtype-1 receptor (AT1R). A major obstacle for AT2R investigations was the lack of specific agonists. Most of the earlier AT2R studies were performed using the peptidic agonist, CG42112A, or the non-peptidic antagonist PD123319. CGP42112A is non-specific for AT2R and in higher concentrations can bind to AT1R. Recently, the development of specific non-peptidic AT2R agonists boosted the efforts in identifying the therapeutic potentials for AT2R stimulation. Unlike AT1R, AT2R is involved in vasodilation via release of bradykinin and nitric oxide, anti-inflammation and healing from injury. Interestingly, the vasodilatory effects of AT2R stimulation were not associated with significant reduction in blood pressure. In the kidney, AT2R stimulation produced natriuresis, increased renal blood flow, and reduced tissue inflammation. In animal studies, enhanced AT2R function led to reduction of cardiac inflammation and fibrosis, and reduced the size of the infarcted area. Similarly, AT2R stimulation demonstrated protective effects in vasculature and brain.