Renal dopamine D1receptor dysfunction is acquired and not inherited in obese Zucker rats

Abstract

In essential hypertension, the defect in renal dopamine (DA) D1receptor 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 D1receptor function in obese Zucker rats. In the present study, we sought to determine whether this D1receptor 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, D1receptor 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 D1receptor expression and a defect in D1receptor-G protein coupling. No such defects in the inhibitory effect of DA on NKA activity, D1receptor 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 D1receptor expression, and D1receptor-G protein uncoupling. These results suggest that defective D1receptor function in obese Zucker rats is not inherited but contributed to by hyperinsulinemia and/or other circulating factors associated with obesity.