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1 Heart and Kidney Institute, University of Houston, Houston, Texas, USA
* To whom correspondence should be addressed. E-mail: mlokhandwala{at}uh.edu.
In essential hypertension, the defect in renal dopamine D1 receptor function is intrinsic to proximal tubules as this phenomenon is also seen in primary proximal tubule cultures from SHR and essential hypertensive patients. Previously we have reported a defect in renal D1 receptor function in obese Zucker rats. In present study we sought to determine whether this D1 receptor dysfunction is intrinsic in these animals. In primary proximal tubular epithelial cells (PTEC) from lean and obese rats, dopamine (DA) inhibited Na, K-ATPase (NKA) activity in PTECs from both groups of rats. The 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 the NKA activity which was accompanied by reduction in D1 receptor expression and 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 to obese serum. Furthermore, chronic insulin treatment of PTECs from lean and obese rats caused attenuation in dopamine-induced NKA inhibition, 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 by hyperinsulinemia and/or other circulating factors associated with obesity.
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