D5 dopamine receptor regulation of phospholipase D.
D(1)-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 D(1)-like receptors (D(1) or D(5)) and whether abnormal regulation of PLD by D(1)-like receptors plays a role in the pathogenesis of hypertension are unknown. The hypothesis that the D(5) receptor is the D(1)-like receptor that inhibits PLD activity and serves to regulate blood pressure was tested using D(5) receptor mutant mice (D(5)(-/-)). We found that in the mouse kidney, PLD2, like the D(5) 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 D(5)(-/-) mice relative to congenic D(5) wild-type (D(5)(+/+)) mice. PLD2, but not PLD1, expression is greater in D(5)(-/-) than in D(5)(+/+) mice. The D(5) receptor agonist fenoldopam decreases PLD2, but not PLD1, expression and activity in human embryonic kidney-293 cells heterologously expressing the human D(5) receptor, effects that are blocked by the D(5) receptor antagonist SCH-23390. These studies show that the D(5) receptor regulates PLD2 activity and expression. The hypertension in the D(5)(-/-) mice is associated with increased PLD expression and activity. Impaired D(5) receptor regulation of PLD2 may play a role in the pathogenesis of hypertension.
Yang
Zhiwei
Z
Department of Physiology and Biophysics, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Washington, DC 20057, USA.
Asico
Laureano D
LD
Yu
Peiying
P
Wang
Zheng
Z
Jones
John E
JE
Bai
Ren-Kui
RK
Sibley
David R
DR
Felder
Robin A
RA
Jose
Pedro A
PA
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007668:Kidney / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism / Q000502:physiology*; D050641:Receptors, Dopamine D5; D014018:Tissue Distribution
C493605:DRD5 protein, human; C493606:Drd5 protein, mouse; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1