D\u3csub\u3e5\u3c/sub\u3e dopamine receptor regulation of phospholipase D

D1-like receptors have been reported to decrease oxidative stress in vascular smooth muscle cells by decreasing phospholipase D (PLD) activity. However, the PLD isoform regulated by D1-like receptors (D1 or D5) and whether abnormal regulation of PLD by D1-like receptors plays a role in the pathogenesis of hypertension are unknown. The hypothesis that the D5 receptor is the D 1-like receptor that inhibits PLD activity and serves to regulate blood pressure was tested using D5 receptor mutant mice (D 5-/-). We found that in the mouse kidney, PLD2, like the D5 receptor, is mainly expressed in renal brush-border membranes, whereas PLD1 is mainly expressed in renal vessels with faint staining in brush-border membranes and collecting ducts. Total renal PLD activity is increased in D5-/- mice relative to congenic D5 wild-type (D5+/+) mice. PLD2, but not PLD1, expression is greater in D5-/- than in D5+/+ mice. The D5 receptor agonist fenoldopam decreases PLD2, but not PLD1, expression and activity in human embryonic kidney-293 cells heterologously expressing the human D5 receptor, effects that are blocked by the D5 receptor antagonist SCH-23390. These studies show that the D 5 receptor regulates PLD2 activity and expression. The hypertension in the D5-/- mice is associated with increased PLD expression and activity. Impaired D5 receptor regulation of PLD2 may play a role in the pathogenesis of hypertension