title: AT₂ receptor activation induces natriuresis and lowers blood pressure.
abstract: BACKGROUND
  Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist.
  
  
  OBJECTIVE
  To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice.
  
  
  RESULTS
  In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial infusion of specific AT2R antagonist PD-123319. C-21 increased fractional excretion of Na(+) (P<0.05) and lithium (P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase. C-21-induced natriuresis was accompanied by an increase in renal interstitial cGMP (P<0.01); C-21-induced increases in urinary sodium excretion and renal interstitial cGMP were abolished by renal interstitial nitric oxide synthase inhibitor l-N(6)-nitroarginine methyl ester or bradykinin B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na(+) retention and lowered blood pressure in the angiotensin II infusion model of experimental hypertension.
  
  
  CONCLUSIONS
  AT2R activation initiates its translocation to the renal proximal tubule cell apical membrane and the internalization of Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase, inducing natriuresis in a bradykinin-nitric oxide-cGMP-dependent manner. Intrarenal AT2R activation prevents Na(+) retention and lowers blood pressure in angiotensin II-dependent hypertension. AT2R activation holds promise as a renal proximal tubule natriuretic/diuretic target for the treatment of fluid-retaining states and hypertension.
authors.affiliation: From the Departments of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Kemp
authors.affiliation: From the Departments of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Howell
authors.affiliation: From the Departments of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.affiliation: From the Departments of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Keller
authors.affiliation: From the Departments of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Pathology (J.J.G.), University of Virginia Health System, Charlottesville.
authors.forename: Shetal H
authors.initials: SH
authors.lastname: Padia
authors.affiliation: From the Departments of Medicine (B.A.K., N.L.H., S.R.K., S.H.P., R.M.C.) and Pathology (J.J.G.), University of Virginia Health System, Charlottesville. rmc4c@virginia.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000235:genetics; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; C494557:N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; D013876:Thiophenes; C065679:icatibant; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester
keywords: blood pressure; kidney tubules, proximal; natriuresis; sodium