Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension

The ability of the dopamine-1 (D-1)-like receptor to stimulate adenylyl cyc lase (AC) and phospholipase C (PLC), inhibit sodium transport in the renal proximal tubule (RPT), and produce natriuresis is attenuated in several rat models of hypertension. Since the inhibitory effect of D-1-like receptors on RPT sodium transport is also reduced in some patients with essential hyp ertension, we measured D-1-like receptor coupling to AC and PLC in cultures of human RPT cells from normotensive (NT) and hypertensive (HT) subjects. Basal cAMP concentrations were the same in NT (n = 6) and HT (n = 4). Howev er, the D-1-like receptor agonist fenoldopam increased cAMP production to a greater extent in NT (maximum response = 6 +/- 1%) than in HT (maximum res ponse = 17 +/- 5%), with a potency ratio of 105. Dopamine also increased cA MP production to a greater extent in NT (32 +/- 3%) than in HT (14 +/- 3%). The fenoldopam-mediated increase in cAMP production was blocked by SCH2339 0 (a D-1-like receptor antagonist) and by antisense D-1 oligonucleotides in both HT and NT, indicating action at the D-1 receptor. The stimulatory eff ects of forskolin and parathyroid hormone-related protein of cAMP accumulat ion were not statistically different in NT and HT, indicating receptor spec ificity and an intact G-protein/AC pathway. The fenoldopam-stimulated PLC a ctivity was not impaired in HT, and the primary sequence and expression of the D-1 receptor were the same in NT and HT. However, D-1 receptor serine p hosphorylation in the basal state was greater in WT than in NT and was not responsive to fenoldopam stimulation in HT. These studies demonstrate the e xpression of D-1 receptors in human RPT cells in culture. The uncoupling of the D-1 receptor in both rats (previously described) and humans (described here) suggests that this mechanism may be involved in the pathogenesis of hypertension; the uncoupling may be due to ligand-independent phosphorylati on of the D-1 receptor in hypertension.