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(Hypertension. 2004;43:376.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D_1A Receptor in Obese Zucker Rats

From the Heart and Kidney Institute, College of Pharmacy, University of Houston, Tex.

Correspondence to Dr M.F. Lokhandwala, Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, TX 77204-5041. E-mail Mlokhandwala{at}uh.edu

Hypertension related to insulin resistance results from increased sodium retention. Dopamine, by activating D_1A receptors in renal proximal tubules, increases sodium excretion. Recently, dopamine has been shown to augment its own signaling by recruiting intracellular D_1A receptors to cell surface in proximal tubules. In this study, we hypothesized that coupling of D_1A receptors to G proteins and dopamine-induced recruitment of D_1A receptors to the plasma membrane are impaired in obese Zucker rats, resulting in a diminished natriuretic and diuretic response to D_1A receptor agonist, SKF-38393. We also examined effects of rosiglitazone (3 mg/kg per day, 15 days) in restoring the defects in D_1A receptor signaling and function in these animals. In obese rats, D_1A receptors did not couple to G proteins, as shown by a lack of fenoldopam-sensitive [³⁵S] GTPS binding. In addition, we observed, by using radioligand binding and immunoblotting, that dopamine recruited D_1A 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 D_1A 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 D_1A receptor signaling and function as treatment with an insulin-sensitizer, rosiglitazone, normalizes these parameters in obese Zucker rats.

Key Words: dopamine • kidney • insulin resistance • obesity

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