Angiotensin AT2 Receptor Stimulation Inhibits Early Renal Inflammation in Renovascular Hypertension
Angiotensin II type 2 receptor (AT2R) counteracts most effects of angiotensin II type 1 receptor (AT1R). We hypothesized that direct AT2R stimulation reduces renal production of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and transforming growth factor-β1 (TGF-β1) and enhances the production of nitric oxide (NO) and cyclic guanosine 3′,5′-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-α, IL-6, NO, and cGMP; renal expression of AT1R, AT2R, TGF-β1, TNF-α, and IL-6 in sham and 2K1C rats treated for 4 days with vehicle, AT2R agonist compound 21 (C21), or AT2R antagonist PD123319 (PD), alone and combined (n=6, 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 AT1R, AT2R, TNF-α, IL-6, TGF-β1 and decreases in NO and cGMP levels. These factors were not influenced by PD treatment. In contrast, C21 caused significant decrease in renal TNF-α, IL-6, TGF-β1 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-α, IL-6, TGF-β1, NO, or cGMP in the nonclipped kidneys of 2K1C animals. We conclude that direct AT2R stimulation reduces early renal inflammatory responses and improves production of NO and cGMP in renovascular hypertension independent of blood pressure reduction.
- Received October 8, 2010.
- Revision received November 2, 2010.
- Accepted November 29, 2010.
- © 2010 American Heart Association, Inc.