Rosiglitazone Treatment Restores Renal Dopamine Receptor Function in Obese Zucker Rats

Abstract

Abstract-Earlier we have reported a defective dopamine D 1 -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.

Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D 1A Receptor in Obese Zucker Rats

“…Previously, we and others have used higher doses of rosiglitazone (Ն10 mg/kg per day) for longer duration (28 days) to improve insulin sensitivity. 11,29,30 However, the present study as well as some recent reports show that even lower doses (3 to 5 mg/kg per day) of rosiglitazone for 7 to 14 days improve insulin sensitivity to the same extent. [31][32][33] In obese rats, fasting blood glucose levels were completely normalized to levels seen in lean rats, and plasma insulin values were reduced to similar extent with both treatment regimens of rosiglitazone.…”

“…10 Blood (Ϸ500 L) was collected from aorta after a midline abdominal incision. 11 Blood glucose values were determined by using Accu-Chek Advantage glucose monitoring system. Plasma insulin levels were measured by a rat insulin radioimmunoassay kit (Linco Research Inc).…”

“…9 We have previously shown that there is reduced abundance and impaired G-protein coupling of cell surface D 1A receptors, resulting in inability of dopamine to inhibit sodium transporters in proximal tubules of insulin-resistant obese Zucker rats. 10 Interestingly, rosiglitazone treatment of obese rats corrected the decrease in cell surface D 1A receptor abundance 11 and the impairment in dopamine-induced inhibition of sodium transporters 11 in proximal tubules. It is possible that impairment in G-protein coupling of D 1A receptors in obese rats is also corrected by rosiglitazone.…”

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

“…However, endogenous renal dopamine production is normal or even increased in obese humans (46), monkeys (43), and rats (39). Therefore, the dopaminergic defect in the obese male rat has been suggested to be at the receptor or postreceptor level (4,5,7,23,24,40). Our finding of decreased renal expression of D1R in obese male rats provides a potential explanation for the reduced D1-like dopaminergic signaling previously reported in the proximal tubule of these rats (5,31).…”

Prediction of Novel Therapeutic Indication for Rosiglitazone Using Its Reported Clinical Sideeffects: Drug Repositioning by Pharmacovigilance Approach

“…These hypothetical data are summarized below in the Table 1 and statistical analysis is depicted in In mild to moderate Alzheimer's disease it may improve the cognitive functions [6][7][8][9] (1) Rosiglitazone may affect the beta amyloid formation by inhibition of beta-secretase enzyme or; In mild to moderate hypertension [10][11][12][13][14] Rosiglitazone may restore the renal dopamine (D1) receptor. Dopamine receptors are linked to phospholipase C and adenylyl cyclase, by coupling with G-protein couple receptor channel.…”