Defective dopamine receptor function in proximal tubules of obese zucker rats.
Some of the pathophysiological consequences of obesity include insulin resistance, increased renal sodium reabsorption, and the development of hypertension. Dopamine promotes renal sodium excretion via activation of D(1)-like receptors present on the proximal tubules. Reduced dopamine-induced natriuresis and a defect in D(1)-like receptor function have been reported in the proximal 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 and control lean Zucker rats. We found that the obese rats were hyperinsulinemic, 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 was reduced in obese rats. The D(1)-like receptors measured by [(3)H]SCH 23390 binding revealed an approximately 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)/11alpha and no change in G(s)alpha in the basolateral membranes of obese rats, dopamine and SKF 38393 failed to stimulate G proteins as measured by [(35)S]GTPgammaS binding in obese rats, suggesting a receptor-G protein coupling defect. We conclude that decrease 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 obese Zucker rats. Such a defect in renal dopamine receptor function may contribute to sodium retention and development of hypertension in obese rats.
Hussain
T
T
Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, TX 77204-5515, USA. THussain@jetson.uh.edu
Beheray
S A
SA
Lokhandwala
M F
MF
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000503:physiopathology*; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D019204:GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D004298:Dopamine