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

摘要

The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D1-like dopamine receptors [dopamine D1 and D5 receptors (D1Rs and D5Rs, respectively)] and the α1A-adrenergic receptor (α1A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na⁺ transport, i.e., natriuresis (via D1Rs and D5Rs) or antinatriuresis (via α1A-ARs). We tested the hypothesis that the D1R/D5R regulates the α1A-AR. D1-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with α1A-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 α_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 α_1A-AR agonist, which by itself induced Na⁺-K⁺-ATPase translocation from the cytosol to the plasma membrane. The α_1A-AR-specific agonist A610603 also minimized the ability of fenoldopam to inhibit Na⁺-K⁺-ATPase activity. To determine the interaction among D₁Rs, D₅Rs, and α_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 D₁-like dopamine receptors to regulate the expression and activity of α_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.