Reduced renal dopamine D1 receptor function in streptozotocin-induced diabetic rats.
Dopamine, via activation of renal D(1) receptors, inhibits the activities of Na-K-ATPase and Na/H exchanger and subsequently increases sodium excretion. Decreased renal dopamine production and sodium excretion are associated with type I diabetes. However, it is not known whether the response to D(1) receptor activation is altered in type I diabetes. The present study was designed to examine the effect of streptozotocin-induced type I diabetes on renal D(1) receptor expression and function. Streptozotocin treatment of Sprague-Dawley rats caused a fourfold increase in plasma levels of glucose along with a significant decrease in insulin levels compared with control rats. Intravenous administration of SKF-38393, a D(1) receptor agonist, caused a threefold increase in sodium excretion in control rats. However, SKF-38393 failed to produce natriuresis in diabetic rats. SKF-38393 caused a concentration-dependent inhibition of Na-K-ATPase activity in renal proximal tubules of control rats. However, the ability of SKF-38393 to inhibit Na-K-ATPase activity was markedly diminished in diabetic rats. D(1) receptor numbers and protein abundance as determined by [(3)H]SCH-23390 ligand binding and Western blot analysis were markedly reduced in diabetic rats compared with control rats. Moreover, SKF-38393 failed to stimulate GTP gamma S binding in proximal tubular membranes from diabetic rats compared with control rats. We conclude that the natriuretic response to D(1) receptor activation is reduced in type I diabetes as a result of a decrease in D(1) receptor expression and defective receptor G protein coupling. These abnormalities may contribute to the sodium retention associated with type I diabetes.
Marwaha
Aditi
A
Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, TX 77204-5041, USA.
Banday
Anees Ahmad
AA
Lokhandwala
Mustafa F
MF
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000254:Sodium-Potassium-Exchanging ATPase