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

• Autor(a) principal: Dias, Juliana
• Data de Publicação: 2014
• Outros Autores: Ferrao, Fernanda M., Axelband, Flavia, Carmona, Adriana K. [UNIFESP], Lara, Lucienne S., Vieyra, Adalberto
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://dx.doi.org/10.1152/ajprenal.00488.2013; http://repositorio.unifesp.br/handle/11600/37581
• topic: ANG-(3-4); kidney proximal tubules; ouabain-resistant Na+-ATPase; spontaneously hypertensive rats; ANG II receptors; heterodimerization

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.