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Title of Journal: Am J Hypertens

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Abbravation: American Journal of Hypertension

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Narnia

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DOI

10.1016/0161-5890(84)90119-6

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0895-7061

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P439 Hypertension and PLD2 regulation by D5 dopa

Authors: Yang Zhiwei Asico Laureano D Yu Peiying Wang Zheng Jones John E Felder Robin A Sibley David R Jose Pedro A
Publish Date: 2005/05/01
Volume: 18, Issue: S4, Pages: 165A-165A
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Abstract

Zhiwei Yang Laureano D Asico Peiying Yu Zheng Wang John E Jones Robin A Felder David R Sibley Pedro A Jose P439 Hypertension and PLD2 regulation by D5 dopamine receptor American Journal of Hypertension Volume 18 Issue S4 May 2005 Page 165A https//doiorg/101016/jamjhyper200503457Phospholipase D PLD whose enzymatic products stimulate NADPH oxidase activity and reactive oxygen species ROS production is regulated by the D5 dopamine receptor D5R but the PLD isoform PLD1 and PLD2 regulated by D5R has not been investigated PLD2 like the D5R is constitutively active In this study we found that in the mouse kidney PLD2 like the D5R is mainly expressed in brush border membranes while PLD1 is mainly expressed in vessels with much less staining in brush border membranes and collecting ducts Because D5R deficient D5/ mice are hypertensive J Neurosci 20022210801 we sought to determine whether D5R regulation of PLD2 is impaired and ROS is increased in D5/ mice Renal PLD activity is increased in D5/ mice 55±052 relative to congenic D5 wild type D5+/+ mice 32±058 n=3 p005 PLD2 but not PLD1 expression is greater in D5/ 60±3 density units DU than in D5+/+ mice 40±3 DU n=6 P005 The NADPH oxidase activity is also increased in D5/ compared with D5+/+ mice We next determined the regulation of PLD2 by D5Rs in HEK293 cells heterologously expressing human D5R HEKhD5R The D5R agonist fenoldopam decreases PLD2 but not PLD1 expression in a receptorspecific and time and dosedependent manner IC50= 008 μM t1/2=57 hours Fenoldopam inhibits NADPH activity and ROS production in PLD1deficient HEKhD5R cells but to a lesser extent than in the empty vectortransfected HEKhD5R cells no effects are noted in PLD2deficient HEKhD5R cells We conclude that dopamine via the D5R inhibits PLD2 activity Deficiency of D5R results in increased PLD2 and NADPH oxidase activities and generation of ROS causing hypertension Indeed inhibition of NADPH oxidase activity normalizes blood pressure in D5/ mice unpublished data

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