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

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Abstract
We have reported recently that the renal angiotensin II type 2 (AT 2 ) 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 AT 2 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 AT 2 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 AT 2 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 AT 2 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 α1-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 AT 2 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 AT 2 receptor–mediated natriuresis in obese but not in lean Zucker rats.