Angiotensin AT ₂ Receptor Stimulation Inhibits Early Renal Inflammation in Renovascular Hypertension

Abstract

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

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

“…[14][15][16][17][18][19][20][21]30 Given its distribution volume of 3 times total body water, its half life of Ϸ4 hours, and a bioavailability of Ϸ30%, 14 this is expected to result in C21 plasma levels ranging from 0.1 to 5.0 mol/L, that is, well within the range applied here. Such levels (up to Ͼ10 000-fold above the reported inhibition constant for the AT 2 receptor) are also in agreement with the fact that C21 induced AT 1 receptormediated effects in vivo, because its inhibition constant for AT 1 receptors is Ͼ10 000 times above that for AT 2 receptors.…”

“…In the absence of AT 1 receptor blockade, no blood pressure-lower-ing effects were observed in stroke-prone hypertensive rats; 2-kidney, 1-clip hypertensive SD rats; post-myocardial infarction Wistar rats; and C57BL/6 mice. [15][16][17][18]20 When infused over a short time period, 300 ng/kg per minute of C21 induced a modest rise in mean arterial pressure (Ϸ4 mm Hg) in male SD rats, which was not seen in combination with PD123319. 21 A 3.3-fold higher dose increased mean arterial pressure by 20 mm Hg in male SHRs in an AT 1 receptordependent manner.…”

“…Administration of C21 in various cardiovascular disease models, including the postmyocardial infarction Wistar rat 15 ; the stroke-prone hypertensive rat 16,17 ; and the 2-kidney, 1-clip hypertensive Sprague-Dawley (SD) rat, 18 resulted in beneficial organ-protective effects.…”

Direct Stimulation of Angiotensin II Type 2 Receptor Enhances Spatial Memory

“…It was also proved by Matavelli et al (2011) that administration of C21 reduced early renal inflammatory response with production of NO and cGMP. These results indicate that the antiinflammatory action of C21 is mainly focused on the prevention of target-organ damage.…”

The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

“…Strikingly, Ang II negatively regulates its classical actions through the angiotensin II type 2 receptors (AT 2 Rs) [5], with this receptor subtype being markedly upregulated in numerous diseased states, including atherosclerosis [6,7], possibly to counterbalance the adverse effects mediated by the AT 1 R. Taken together, these actions highlight the potential of the AT 2 R as a key therapeutic target. With numerous studies focusing on the role of the AT 2 R in the non-diabetes setting [8][9][10], the vascular actions of this receptor in the context of diabetes still remains unclear. Given our previous findings that selective activation of the AT 2 R by a novel non-peptide agonist, Compound 21 (C21), significantly ameliorated the progression of nephropathy in an insulin-deficient model [11], we aimed to further investigate the protective role of C21 on macrovascular disease in this diabetes model.…”