title: Angiotensin II type 2 receptor agonist directly inhibits proximal tubule sodium pump activity in obese but not in lean Zucker rats.
abstract: 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 micromol/L), not the angiotensin II type 1 antagonist losartan (1 micromol/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 micromol/L), the NO synthase inhibitor NG-nitro-L-arginine methyl ester (100 micromol/L), and the protein kinase G inhibitor K1388 (2 micromole/L). CGP42112 (10 nmol/L) caused an increase in serine phosphorylation of NKA alpha1-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 micromol/L), NG-nitro-L-arginine methyl ester (100 micromol/L), and 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (10 micromol/L) but not by losartan (1 micromol/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.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204-5037, USA.
authors.forename: Amer C
authors.initials: AC
authors.lastname: Hakam
authors.forename: Tahir
authors.initials: T
authors.lastname: Hussain
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013851:Thinness / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D009566:Nitrates; D009573:Nitrites; D009842:Oligopeptides; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C060894:CGP 42112A; C073402:PD 123319; D000242:Cyclic AMP; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP