Abstract
The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D&sub1;-like dopamine receptors [dopamine D&sub1; and D₅ receptors (D&sub1;Rs and D₅Rs, respectively)] and the α&sub1;A-adrenergic receptor (α&sub1;A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na(+) transport, i.e., natriuresis (via D&sub1;Rs and D5Rs) or antinatriuresis (via α&sub1;A-ARs). We tested the hypothesis that the D&sub1;R/D₅R regulates the α&sub1;A-AR. D&sub1;-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with α&sub1;A-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D&sub1;R/D₅R agonist fenoldopam resulted in decreased D&sub1;R and D₅R expression but increased α&sub1;A-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 α&sub1;A-AR agonist, which by itself induced Na(+)-K(+)-ATPase translocation from the cytosol to the plasma membrane. The α&sub1;A-AR-specific agonist A610603 also minimized the ability of fenoldopam to inhibit Na(+)-K(+)-ATPase activity. To determine the interaction among D&sub1;Rs, D₅Rs, and α&sub1;A-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 D&sub1;R-D₅R double-knockout mice. Our results demonstrate the ability of the D&sub1;-like dopamine receptors to regulate the expression and activity of α&sub1;A-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.