The dopamine D1 receptors (D1R), expressed in renal proximal tubules, participate in the regulation of sodium transport. A defect in the coupling of the D1R to its G protein/effector complex in renal tubules has been reported in various conditions associated with oxidative stress. As GRKs are known to play important role in D1R desensitization, we tested the hypothesis that increased oxidative stress in obese Zucker rats may cause GRK2 upregulation and subsequent D1R dysfunction. Lean and obese rats were given normal diet or diet supplemented with antioxidant lipoic acid for two weeks. Compared to lean, obese rats exhibited oxidative stress, D1R were uncoupled from Gq/11 at basal level and SKF38393 failed to elicit D1R G protein-coupling, stimulate phospholipase C (PLC) and inhibit Na/K-ATPase activity. These animals showed increased basal PKC activity and membranous translocation of GRK2 and increased GKR2-Gq/11 interaction and D1R serine-phosphorylation. Enzymatic dephosphorylation of D1R restored SKF38393-induced adenylyl cyclase stimulation but not PLC activation. Treatment of obese rats with lipoic acid restored D1R G protein-coupling and SKF38393-induced PLC stimulation and Na/K-ATPase inhibition. Lipoic acid treatment also normalized PKC activity, GRK2 sequestration and GKR2-Gq/11 interaction. In conclusion, these data show that oxidative stress increases PKC activity causing GRK2 membranous translocation. GRK2 interacts with Gq/11 and acts, at least in part, as a RGS leading to the D1R Gq/11-uncoupling causing inability of SKF38393 to stimulate PLC and inhibit Na/K-ATPase. Lipoic acid while reducing oxidative stress, normalized PKC activity and restored D1R-Gq/11-PLC signaling and ability of SKF38393 to inhibit Na/K-ATPase activity.