Defective dopamine receptor function in proximal tubules of obese Zucker rats

Some of the pathophysiological consequences of obesity include insulin resi stance, increased renal sodium reabsorption, and the development of hyperte nsion. Dopamine promotes renal sodium excretion via activation of D-1-like receptors present on the proximal tubules. Reduced dopamine-induced natriur esis and a defect in D-1-like receptor function have been reported in the p roximal tubules of hypertensive animals. The present study investigated D-1 -like dopamine receptors and associated G proteins as the initial signaling components in the proximal tubular basolateral membranes of obese Zucker a nd control lean Zucker rats. We found that the obese rats were hyperinsulin emic, hyperglycemic, and hypertensive compared with the lean rats. Dopamine produced concentration-dependent inhibition of Na,K-ATPase activity in the proximal tubules of lean rats, whereas the inhibitory effect of dopamine w as reduced in obese rats. The D-1-like receptors measured by [H-3]SCH 23390 binding revealed an approximate to 45% decrease in B-max without a change in K-d in the basolateral membranes of obese rats compared with lean rats. Although we found an increase in G(q)/11 alpha and no change in G(s)alpha i n the basolateral membranes of obese rats, dopamine and SKF 38393 failed to stimulate G proteins as measured by [S-35]GTP gamma S binding in obese rat s, suggesting a receptor-G protein coupling defect. We conclude that decrea se in D-1-like dopamine receptor binding sites and diminished activation of G proteins, resulting perhaps from defective coupling, led to the reduced inhibition by dopamine of Na,K-ATPase activity in the proximal tubules of o bese Zucker rats. Such a defect in renal dopamine receptor function may con tribute to sodium retention and development of hypertension in obese rats.