title: Rosiglitazone treatment restores renal dopamine receptor function in obese Zucker rats.
abstract: Earlier we have reported a defective dopamine D1-like receptor function, which was accompanied by a decrease in D1 receptor numbers and the inability of dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules of hyperinsulinemic obese Zucker rats. The present study was designed to test the hypothesis that the defect in dopamine receptor function is a result of hyperinsulinemia in obese rats. We designed experiments to study D1 receptor function in obese Zucker rats treated with rosiglitazone, as it lowers plasma insulin by improving insulin sensitivity. A group of untreated lean and obese rats served as controls. Rosiglitazone treatment (10 mg/kg orally, 4 weeks) caused significant decreases in plasma insulin, blood glucose, and blood pressure while causing an increase in renal sodium excretion compared with untreated obese rats. In the isolated proximal tubules obtained from untreated lean rats, dopamine caused concentration-dependent inhibition of the Na,K-ATPase activity, but this inhibitory effect was absent in untreated obese rats. In rosiglitazone-treated obese rats, the inhibitory effect of dopamine on Na,K-ATPase was significantly restored. This was accompanied by a complete restoration of D1 receptor numbers in proximal tubular membranes of treated obese rats. In another set of experiments, treatment of primary proximal tubule epithelial cells in culture medium with insulin caused a significant decrease in the D1 receptor abundance, suggesting a direct role of insulin on D1 receptor regulation. We conclude that hyperinsulinemia causes downregulation of D1 receptor function and lowering of plasma insulin levels leads to restoration of renal D1 receptor function.
authors.affiliation: Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Tex 77204, USA.
authors.forename: Dhananjay N
authors.initials: DN
authors.lastname: Umrani
authors.forename: Anees A
authors.initials: AA
authors.lastname: Banday
authors.forename: Tahir
authors.initials: T
authors.lastname: Hussain
authors.forename: Mustafa F
authors.initials: MF
authors.lastname: Lokhandwala
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006946:Hyperinsulinism / Q000097:blood / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D000077154:Rosiglitazone; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
chemical_list: D001552:Benzazepines; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D017447:Receptors, Dopamine D1; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D004298:Dopamine