title: Oxidative stress causes renal dopamine D1 receptor dysfunction and hypertension via mechanisms that involve nuclear factor-kappaB and protein kinase C.
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-kappaB 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-kappaB translocation, PKC activity and expression, GRK-2 sequestration, and D1 receptor serine phosphorylation. In conclusion, these results show that oxidative stress activates NF-kappaB, 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.
authors.affiliation: Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas , USA.
authors.forename: Anees Ahmad
authors.initials: AA
authors.lastname: Banday
authors.forename: Fatima Rizwan
authors.initials: FR
authors.lastname: Fazili
authors.forename: Mustafa F
authors.initials: MF
authors.lastname: Lokhandwala
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019328:Buthionine Sulfoximine; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D054769:G-Protein-Coupled Receptor Kinase 2; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism
chemical_list: C029152:G-substrate; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1; D019328:Buthionine Sulfoximine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D011493:Protein Kinase C; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D000262:Adenylyl Cyclases