Oxidative stress causes renal dopamine D1 receptor dysfunction and hypertension via mechanisms that involve nuclear factor-kappaB and protein kinase C.
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.
Banday
Anees Ahmad
AA
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas , USA.
Fazili
Fatima Rizwan
FR
Lokhandwala
Mustafa F
MF
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
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