ANG-(3-4) inhibits renal Na+-ATPase in hypertensive rats through a mechanism that involves dissociation of ANG II receptors, heterodimers, and PKA

Autor(es)

Dias, Juliana ^{[1, 2]} ; Ferrao, Fernanda M. ^{[1, 2]} ; Axelband, Flavia ^{[1, 2]} ; Carmona, Adriana K. ^[3] ; Lara, Lucienne S. ^{[1, 4]} ; Vieyra, Adalberto ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Natl Inst Sci & Technol Struct Biol & Bioimaging, Rio De Janeiro - Brazil

^[2] Univ Fed Rio de Janeiro, Carlos Chagas Filho Inst Biophys, BR-21941902 Rio De Janeiro - Brazil

^[3] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo - Brazil

^[4] Univ Fed Rio de Janeiro, Inst Biomed Sci, BR-21941902 Rio De Janeiro - Brazil

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 306, n. 8, p. F855-F863, APR 2014.
• Citações Web of Science: 12

Resumo

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 AT(2) receptor (AT(2)R) antagonist and a specific PKA inhibitor, respectively, abrogated this inhibition, indicating that AT(2)R 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 AT(2)R and PKA. Tubular membranes from WKY rats had higher levels of AT(2)R/AT(1)R 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. (AU)

• Processo FAPESP: 12/50475-2 - Estudo de enzimas proteolíticas envolvidas em processos fisiológicos e fisiopatológicos
• Beneficiário: Adriana Karaoglanovic Carmona
• Modalidade de apoio: Auxílio à Pesquisa - Regular