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Control Mechanisms of Renin Synthesis and Release: A 21st Century Perspective

NO and cGMP mediate angiotensin AT₂ receptor-induced renal renin inhibition in young rats

¹Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; and ²Department of Biochemistry, Vanderbilt University, Nashville, Tennessee

Submitted 10 January 2007 ; accepted in final form 31 July 2007

We hypothesized that angiotensin subtype-2 receptor (AT₂R) inhibits renal renin biosynthesis in young rats via nitric oxide (NO). We monitored changes in renal NO, cGMP, renal renin content (RRC), and ANG II in 4-wk-old rats in response to low sodium (LNa⁺) intake alone and combined with 8-h direct renal cortical administration of AT₁ receptor blocker valsartan (VAL), AT₂R blocker PD123319 (PD), NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME), NO donor S-nitroso-N-acetyl penicillamine (SNAP), or guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,2-] quinoxaline-1-one (ODQ). In addition, we monitored renal endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) in response to VAL or PD. LNa⁺, VAL, PD, L-NAME, and ODQ increased RRC, ANG II, and renin mRNA. PD and L-NAME decreased NO and cGMP, while SNAP reduced RRC, ANG II, renin mRNA, and reversed the effects of PD. PD also reduced eNOS and nNOS protein and mRNA. Combined treatment with PD, L-NAME, or ODQ and VAL reversed the effects of VAL and caused further increase in RRC, ANG II, renin mRNA, and protein. ODQ reversed the effects of SNAP. These data demonstrate that the renal AT₂ receptor decreases renal renin biosynthesis and ANG II production in young rats. Reversal of the PD effects by SNAP and SNAP effects by ODQ confirms that NO and cGMP mediate the AT₂ receptor inhibition of renal renin production.

angiotensin II; AT₁ receptor; nitric oxide; valsartan

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