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(Hypertension. 2006;47:1117.)
© 2006 American Heart Association, Inc.

Original Articles

Angiotensin II Type 2 Receptor Agonist Directly Inhibits Proximal Tubule Sodium Pump Activity in Obese But Not in Lean Zucker Rats

From the Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Tex.

Correspondence to Tahir Hussain, Department of Pharmacological and Pharmaceutical Sciences, Science and Research Bldg 2, University of Houston, 4800 Calhoun, Houston, TX 77204-5037. E-mail thussain2{at}uh.edu

We have reported recently that the renal angiotensin II type 2 (AT₂) receptors are upregulated and involved in promoting natriuresis/diuresis in obese but not in lean Zucker rats. In the present study, we tested the hypothesis that there is an enhanced AT₂ receptor signaling via NO/cGMP pathway leading to greater inhibition of the Na⁺, K⁺-ATPase (NKA) activity in the proximal tubules (PT) of obese rather than lean Zucker rats. The AT₂ agonist CGP42112 (0.1 to 100 nmol/L) inhibited (33% at 100 nmol/L) the NKA activity in the PTs of obese but not in lean Zucker rats. The AT₂ antagonist PD123319 (1 µmol/L), not the angiotensin II type 1 antagonist losartan (1 µmol/L), significantly diminished the CGP42112-induced inhibition of the NKA activity in obese rats. The AT₂ agonist (10 nmol/L)–induced NKA inhibition was abolished by the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 µmol/L), the NO synthase inhibitor N^G-nitro-L-arginine methyl ester (100 µmol/L), and the protein kinase G inhibitor K1388 (2 µmole/L). CGP42112 (10 nmol/L) caused an increase in serine phosphorylation of NKA 1-subunit in PT of obese rats. Measurement of cGMP and NO revealed that CGP42112 (0.1 to 100 nmol/L) increased cGMP and NO accumulation in the PTs of obese but not lean rats. The CGP42112-induced stimulation of NO and cGMP was blocked by PD123319 (1 µmol/L), N^G-nitro-L-arginine methyl ester (100 µmol/L), and 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 µmol/L) but not by losartan (1 µmol/L). The data suggest that the AT₂ receptor activation via stimulation of the NO/cGMP/protein kinase G pathway directly inhibits the tubular NKA activity that provides as a mechanism responsible for the AT₂ receptor–mediated natriuresis in obese but not in lean Zucker rats.

Key Words: diabetes mellitus • hypertension, sodium-dependent • kidney • sodium • epithelium

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