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Intrarenal Dopamine D1-Like Receptor Stimulation Induces Natriuresis via an Angiotensin Type-2 Receptor Mechanism

We explored the effects of direct renal interstitial stimulation of dopamine D1-like receptors with fenoldopam, a selective D1-like receptor agonist, on renal sodium excretion and angiotensin type-2 (AT2) receptor expression and cellular distribution in rats on a high-sodium intake. In contrast to vehicle-infused rats, sodium excretion increased in fenoldopam-infused rats during each of three 1-hour experimental periods (<0.001). Blood pressure was unaffected by vehicle or fenoldopam. In plasma membranes of renal cortical cells, fenoldopam increased D1 receptor expression by 38% (P<0.05) and AT2 receptor expression by 69% (P<0.01). In plasma membranes of renal proximal tubule cells, fenoldopam increased AT2 receptor expression by 108% (P<0.01). In outer apical membranes of proximal tubule cells, fenoldopam increased AT2 receptor expression by 59% (P<0.01). No significant change in total AT2 receptor protein expression was detectable in response to fenoldopam. Fenoldopam-induced natriuresis was abolished when either PD-123319, a specific AT2 receptor antagonist, or SCH-23390, a potent D1-like receptor antagonist, was coinfused with F (P<0.001). In summary, direct renal D1-like receptor activation increased urinary sodium excretion and the plasma membrane expression of AT2 receptors in renal cortical and proximal tubule cells. D1-like receptor–induced natriuresis was abolished by intrarenal AT2 receptor inhibition. These findings suggest that dopaminergic regulation of sodium excretion involves recruitment of AT2 receptors to the outer plasma membranes of renal proximal tubule cells and that dopamine-induced natriuresis requires AT2 receptor activation.