Rosiglitazone restores G-protein coupling, recruitment, and function of renal dopamine D1A receptor in obese Zucker rats.
Hypertension related to insulin resistance results from increased sodium retention. Dopamine, by activating D1A receptors in renal proximal tubules, increases sodium excretion. Recently, dopamine has been shown to augment its own signaling by recruiting intracellular D1A receptors to cell surface in proximal tubules. In this study, we hypothesized that coupling of D1A receptors to G proteins and dopamine-induced recruitment of D1A receptors to the plasma membrane are impaired in obese Zucker rats, resulting in a diminished natriuretic and diuretic response to D1A receptor agonist, SKF-38393. We also examined effects of rosiglitazone (3 mg/kg per day, 15 days) in restoring the defects in D1A receptor signaling and function in these animals. In obese rats, D1A receptors did not couple to G proteins, as shown by a lack of fenoldopam-sensitive [35S] GTPgammaS binding. In addition, we observed, by using radioligand binding and immunoblotting, that dopamine recruited D1A receptors to cell surface in lean Zucker rats but failed to do so in obese rats. Rosiglitazone treatment resulted in restoration of G-protein coupling of D1A receptors and their recruitment by dopamine in obese rats similar to that seen in lean rats. Furthermore, SKF-38393 failed to increase natriuresis and diuresis in obese rats compared with lean rats. However, in rosiglitazone-treated obese rats, SKF-38393 elicited a diuretic and natriuretic response similar to that in lean rats. Collectively, these results suggest that insulin resistance may be responsible for impaired renal dopamine D1A receptor signaling and function as treatment with an insulin-sensitizer, rosiglitazone, normalizes these parameters in obese Zucker rats.
Trivedi
Meghna
M
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Tex 77204-5041, USA.
Marwaha
Aditi
A
Lokhandwala
Mustafa
M
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000652:urine; D021381:Protein Transport; D051381:Rats; D011924:Rats, Zucker; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D012964:Sodium / Q000652:urine; D045162:Thiazolidinediones / Q000494:pharmacology*; D014556:Urine
D001786:Blood Glucose; D007328:Insulin; D017447:Receptors, Dopamine D1; D045162:Thiazolidinediones; C098593:dopamine D1A receptor; D000077154:Rosiglitazone; D005576:Colforsin; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D012964:Sodium; D020962:Heterotrimeric GTP-Binding Proteins; D004298:Dopamine