Mitogen-activated protein kinase upregulation reduces renal D1 receptor affinity and G-protein coupling in obese rats

Reactive oxygen species play a key role in pathophysiology of cardiovascular diseases by modulating G-protein-coupled receptor signaling. We have shown that treatment of animal models of diabetes and aging with tempol decreases oxidative stress and restores renal dopamine D1 receptor (D1R) function. In present study, we determined whether oxidation of D1R and upregulation of mitogen-activated protein kinases (MAPK) were responsible for decreased D1R signaling in obese animals. Male lean and obese Zucker rats were supplemented with antioxidants tempol or lipoic acid for 2 weeks. Compared to lean, obese animals were hyperglycemic and hyperinsulinemic with increased oxidative stress, D1R oxidation and decreased glutathione levels. These animals had decreased renal D1R affinity and basal coupling to G-proteins. SKF-38393, a D1R agonist failed to stimulate G-proteins and adenylyl cyclase. Obese animals showed marked increase in renal MAPK activities. Treatment of obese rats with tempol or lipoic acid decreased blood glucose, reduced oxidative stress, and restored the basal D1R G-protein coupling. Antioxidants also normalized MAPK activities and restored D1R affinity and SKF-38393 induced D1R G-protein coupling and adenylyl cyclase stimulation. These studies show that D1R oxidation and MAPK upregulation contribute to D1R dysfunction in obese animals. Consequently, antioxidants while reducing the oxidative stress normalize the MAPK activities and restore D1R signaling.