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Diabetes 54:2219-2226, 2005
© 2005 by the American Diabetes Association, Inc.
Tempol Reduces Oxidative Stress, Improves Insulin Sensitivity, Decreases Renal Dopamine D1 Receptor Hyperphosphorylation, and Restores D1 Receptor–G-Protein Coupling and Function in Obese Zucker Rats
From the Heart and Kidney Institute, University of Houston, Houston, Texas
Oxidative stress plays a pathogenic role in hypertension, particularly the one associated with diabetes and obesity. Here, we test the hypothesis that renal dopamine D1 receptor dysfunction in obese Zucker rats is caused by oxidative stress. One group each from lean and obese Zucker rats received tempol, a superoxide dismutase mimetic in drinking water for 2 weeks. Obese animals were hypertensive, hyperglycemic, and hyperinsulinemic, exhibited renal oxidative stress, and increased protein kinase C activity. Also, there was hyperphosphorylation of D1 receptor, defective receptor–G-protein coupling, blunted dopamine-induced Na+-K+-ATPase inhibition, and diminished natriuretic response to D1 receptor agonist, SKF-38393. However, obese animals had elevated levels of plasma nitric oxide and urinary cGMP. In addition, L-N-nitroarginine and sodium nitroprusside showed similar effect on blood pressure in lean and obese rats. In obese animals, tempol reduced blood pressure, blood glucose, insulin, renal oxidative stress, and protein kinase C activity. Tempol also decreased D1 receptor phosphorylation and restored receptor G-protein coupling. Dopamine inhibited Na+-K+-ATPase activity, and SKF-38393 elicited a natriuretic response in tempol-treated obese rats. Thus in obese Zucker rats, tempol ameliorates oxidative stress and improves insulin sensitivity. Consequently, hyperphosphorylation of D1 receptor is reduced, leading to restoration of receptor–G-protein coupling and the natriuretic response to SKF-38393.
Address correspondence and reprint requests to Dr. Mustafa F. Lokhandwala, College of Pharmacy, University of Houston, Houston TX 77204. E-mail: mlokandwala{at}uh.edu
Abbreviations:
CML, carboxymethyllysine; DAG, 1,2-diacylglycerol; FENa, fractional excretion of sodium; GFR, glomerular filtration rate; GRK, G-protein–coupled receptor kinase; L-NNA, L-N-nitroarginine; MDA, malondialdehyde; PKC, protein kinase C; SNP, sodium nitroprusside; SOD, superoxide dismutase; [35S]GTP
S, guanosine 5'-(-thio)triphosphate[35S]
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