title: ANG-(3-4) inhibits renal Na+-ATPase in hypertensive rats through a mechanism that involves dissociation of ANG II receptors, heterodimers, and PKA.
abstract: The physiological roles of ANG-(3-4) (Val-Tyr), a potent ANG II-derived peptide, remain largely unknown. The present study 1)investigates whether ANG-(3-4) modulates ouabain-resistant Na(+)-ATPase resident in proximal tubule cells and 2) verifies whether its possible action on pumping activity, considered the fine tuner of Na(+) reabsorption in this nephron segment, depends on blood pressure. ANG-(3-4) inhibited Na(+)-ATPase activity in membranes of spontaneously hypertensive rats (SHR) at nanomolar concentrations, with no effect in Wistar-Kyoto (WKY) rats or on Na(+)-K(+)-ATPase. PD123319 (10(-7) M) and PKA(5-24) (10(-6) M), an AT2 receptor (AT2R) antagonist and a specific PKA inhibitor, respectively, abrogated this inhibition, indicating that AT2R and PKA are central in this pathway. Despite the lack of effect of ANG-(3-4) when assayed alone in WKY rats, the peptide (10(-8) M) completely blocked stimulation of Na(+)-ATPase induced by 10(-10) M ANG II in normotensive rats through a mechanism that also involves AT2R and PKA. Tubular membranes from WKY rats had higher levels of AT2R/AT1R heterodimers, which remain associated in 10(-10) M ANG II and dissociate to a very low dimerization state upon addition of 10(-8) M ANG-(3-4). This lower level of heterodimers was that found in SHR, and heterodimers did not dissociate when the same concentration of ANG-(3-4) was present. Oral administration of ANG-(3-4) (50 mg/kg body mass) increased urinary Na(+) concentration and urinary Na(+) excretion with a simultaneous decrease in systolic arterial pressure in SHR, but not in WKY rats. Thus the influence of ANG-(3-4) on Na(+) transport and its hypotensive action depend on receptor association and on blood pressure.
authors: Carlos Chagas Filho Institute of Biophysics, Federal Univ. of Rio de Janeiro and National Institute of Science and Technology for Structural Biology and Bioimaging, Rio de Janeiro 21941-902, Brazil. avieyra@biof.ufrj.br.
authors: Juliana
authors: J
authors: Dias
authors: Fernanda M
authors: FM
authors: Ferrão
authors: Flavia
authors: F
authors: Axelband
authors: Adriana K
authors: AK
authors: Carmona
authors: Lucienne S
authors: LS
authors: Lara
authors: Adalberto
authors: A
authors: Vieyra
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000652:urine; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D027682:Cation Transport Proteins; D004151:Dipeptides; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C414029:valyltyrosine; C073402:PD 123319; D010042:Ouabain; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ANG II receptors; ANG-(3–4); heterodimerization; kidney proximal tubules; ouabain-resistant Na+-ATPase; spontaneously hypertensive rats