Dopamine D1-like receptors regulate the α1A-adrenergic receptor in human renal proximal tubule cells and D1-like dopamine receptor knockout mice

Thehomeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D-1-like dopamine receptors [dopamine D-1 and D-5 receptors (D(1)Rs and D(5)Rs, respectively)] and the alpha(1A)-adrenergic receptor (alpha(1A)-AR) are expressed in the renal proximal tubule and engender opposing effects on Na+ transport, i.e., natriuresis (via D(1)Rs and D(5)Rs) or antinatriuresis (via alpha(1A)-ARs). We tested the hypothesis that the D1R/D5R regulates the alpha(1A)-AR. D-1-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with alpha(1A)-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D1R/D5R agonist fenoldopam resulted in decreased D1R and D5R expression but increased alpha(1A)-AR abundance in the plasma membrane. Short-term fenoldopam treatment stimulated the translocation of Na+-K+-ATPase from the plasma membrane to the cytosol that was partially reversed by an alpha(1A)-AR agonist, which by itself induced Na+-K+-ATPase translocation from the cytosol to the plasma membrane. The alpha(1A)-AR-specific agonist A610603 also minimized the ability of fenoldopam to inhibit Na+ K+-ATPase activity. To determine the interaction among D(1)Rs, D(5)Rs, and alpha(1A)-ARs in vivo, we used phenylephrine and A610603 to decrease Na+ excretion in several D1-like dopamine receptor knockout mouse strains. Phenylephrine and A61603 treatment resulted in a partial reduction of urinary Na+ excretion in wild-type mice and its abolition in D1R knockout, D5R knockout, and D1R-D5R double-knockout mice. Our results demonstrate the ability of the D-1-like dopamine receptors to regulate the expression and activity of alpha(1A)-AR. Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti-and pro-hypertensive systems.