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2004 CARDIOVASCULAR AND KIDNEY INVESTIGATORS MEETING

D₅ dopamine receptor regulation of phospholipase D

¹Department of Physiology and Biophysics, ²Department of Pediatrics, ³Institute for Molecular and Human Genetics, Georgetown University Medical Center, Washington, District of Columbia; ⁴National Institute Neurological Disorders and Stroke, Bethesda, Maryland; and ⁵Department of Pathology, The University of Virginia Center for the Health Sciences, Charlottesville, Virginia

Submitted 24 June 2004 ; accepted in final form 18 August 2004

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 D₁-like receptor that inhibits PLD activity and serves to regulate blood pressure was tested using D₅ receptor mutant mice (D₅^–/–). 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 D₅ 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.

hypertension

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