Mechanisms of Dopamine D 1 and Angiotensin Type 2 Receptor Interaction in Natriuresis

Abstract

Renal dopamine D 1 –like receptors (D 1 Rs) and angiotensin type 2 receptors (AT 2 Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor–mediated tubular sodium reabsorption. Here we explore the mechanisms of D 1 R and AT 2 R interactions in natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D 1 R agonist fenoldopam induced a natriuretic response that was abolished by the AT 2 R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT 2 Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D 1 R activation induces natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT 2 R recruitment and AT 2 R-mediated natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D 1 R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT 2 Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D 1 R-induced natriuresis requires AT 2 R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D 1 Rs and AT 2 Rs act in concert to promote sodium excretion in vivo.