Oxidative Stress Causes Renal Dopamine D1 Receptor... : Journal of the American Society of Nephrology (original) (raw)
Cell and Transport Physiology
Oxidative Stress Causes Renal Dopamine D1 Receptor Dysfunction and Hypertension via Mechanisms That Involve Nuclear Factor-κB and Protein Kinase C
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas
Address correspondence to: Dr. Mustafa F. Lokhandwala, Department of Pharmacology, University of Houston, 4800 Calhoun Road, S & R-2 Building, Houston, TX 77204. Phone: 713-743-3777; Fax: 713-743-1230; E-mail: [email protected]
Accepted March 1, 2007
Received December 19, 2006
Abstract
Renal dopamine, via activation of D1 receptors, plays a role in maintaining sodium homeostasis and BP. There exists a defect in renal D1 receptor function in hypertension, diabetes, and aging, conditions that are associated with oxidative stress. However, the exact underlying mechanism of the oxidative stress–mediated impaired D1 receptor signaling and hypertension is not known. The effect of oxidative stress on renal D1 receptor function was investigated in healthy animals. Male Sprague-Dawley rats received tap water (vehicle) and 30 mM L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mM tempol for 2 wk. Compared with vehicle, BSO treatment caused oxidative stress and increase in BP, which was accompanied by defective D1 receptor G-protein coupling and loss of natriuretic response to SKF38393. BSO treatment also increased NF-κB nuclear translocation, protein kinase C (PKC) activity and expression, G-protein–coupled receptor kinase-2 (GRK-2) membranous translocation, and D1 receptor serine phosphorylation. In BSO-treated rats’ supplementation of tempol decreased oxidative stress, normalized BP, and restored D1 receptor G-protein coupling and natriuretic response to SKF38393. Tempol also normalized NF-κB translocation, PKC activity and expression, GRK-2 sequestration, and D1 receptor serine phosphorylation. In conclusion, these results show that oxidative stress activates NF-κB, causing an increase in PKC activity, which leads to GRK-2 translocation and subsequent D1 receptor hyper–serine phosphorylation and uncoupling. The functional consequence of this phenomenon was the inability of SKF38393 to inhibit Na/K-ATPase activity and promote sodium excretion, which may have contributed to increase in BP. Tempol reduced oxidative stress and thereby restored D1 receptor function and normalized BP.
Copyright © 2007 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
Full Text Access for Subscribers:
