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Renal dopamine D₁ receptor dysfunction is acquired and not inherited in obese Zucker rats

Heart and Kidney Institute, University of Houston, Houston, Texas 77204

Submitted 10 November 2003 ; accepted in final form 8 March 2004

In essential hypertension, the defect in renal dopamine (DA) D₁ receptor function is intrinsic to proximal tubules as this phenomenon is also seen in primary proximal tubule cultures from spontaneously hypertensive rats (SHR) and essential hypertensive patients. Previously, a defect was reported in renal D₁ receptor function in obese Zucker rats. In the present study, we sought to determine whether this D₁ receptor dysfunction is intrinsic in these animals. In primary proximal tubular epithelial cells (PTECs) from lean and obese rats, DA inhibited Na-K-ATPase (NKA) activity in PTECs from both groups of rats. Basal NKA activity, D₁ receptor protein expression, and their coupling to G proteins were similar in cells from both groups. However, when PTECs from lean and obese rats were cultured in 20% serum from obese rats, DA failed to inhibit NKA activity, which was accompanied by a reduction in D₁ receptor expression and a defect in D₁ receptor-G protein coupling. No such defects in the inhibitory effect of DA on NKA activity, D₁ receptor numbers, or coupling were seen when PTECs from both lean and obese rats were grown in 20% serum from lean or rosiglitazone-treated obese (RTO) rats. RTO rat serum had normal blood glucose and reduced plasma levels of insulin compared with serum from obese rats. Furthermore, chronic insulin treatment of PTECs from lean and obese rats caused an attenuation in DA-induced NKA inhibition, a decrease in D₁ receptor expression, and D₁ receptor-G protein uncoupling. These results suggest that defective D₁ receptor function in obese Zucker rats is not inherited but contributed to by hyperinsulinemia and/or other circulating factors associated with obesity.

G proteins; insulin; Na-K-ATPase; obesity; rosiglitazone

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