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(Hypertension. 2008;51:360.)
© 2008 American Heart Association, Inc.

Original Articles

Differential D₁ and D₅ Receptor Regulation and Degradation of the Angiotensin Type 1 Receptor

From the Department of Pathology (J.J.G., X.W., R.A.F.), University of Virginia, Charlottesville; and the Department of Pediatrics (P.A.J.), Georgetown University Medical Center, Washington, DC.

Correspondence to Robin A. Felder, Department of Pathology, University of Virginia, PO Box 800403, Charlottesville, VA 22908. E-mail rfelder{at}virginia.edu

Renal sodium transport is increased by the angiotensin type 1 receptor (AT₁R), which is counterregulated by dopamine via unknown mechanisms involving either the dopamine type 1 (D₁R) or dopamine type 5 receptor (D₅R) that belong to the D₁-like receptor family of dopamine receptors. We hypothesize that the D₁R and D₅R differentially regulate AT₁R protein expression and signaling, which may have important implications in the pathogenesis of essential hypertension. D₁R and D₅R share the same agonists and antagonists; therefore, the selective effects of either D₁R or D₅R stimulation on AT₁R expression in human renal proximal tubule cells were determined using antisense oligonucleotides selective to either D₁R or D₅R. We also determined the role of receptor tyrosine kinase and the proteosome on the D₁R/D₅R-mediated effects on AT₁R expression and internalization. In renal proximal tubule cells, D₅R (not D₁R) decreased AT₁R expression (half-life: 0.47±0.18 hours) and AT₁R-mediated extracellular signal–regulated kinase 1/2 phosphorylation (232±18.9 U with angiotensin II [10^–7 mol/L] versus 81±8.9 U with angiotensin II [10^–7 mol/L] and fenoldopam [D₁R/D₅R agonist; 10^–6 mol/L; P<0.05; n=6). The fenoldopam-induced decrease in AT₁R expression was reversed by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3,4-d) pyrimidine (c-Src tyrosine-kinase inhibitor) and clasto-lactacystin β-lactone (proteasome inhibitor), demonstrating that the fenoldopam-mediated decrease in total cell AT₁R expression is a result of a c-Src- and proteasome-dependent process. D₅R stimulation decreases AT₁R expression and is c-Src and proteasome dependent. The discovery of differential regulation by D₁R and D₅R opens new avenues for the development of agonists selective to either receptor subtype as targeted antihypertensive agents that can decrease AT₁R-mediated antinatriuresis.

Key Words: dopamine 1–like receptor • angiotensin type 1 receptor • human renal proximal tubular cells • D₁ receptor • D₅ receptor