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Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes

¹Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, District of Columbia 20057; and ²Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892

Submitted 9 April 2003 ; accepted in final form 4 August 2003

Uncontrolled diabetes mellitus (DM) is associated with copious water and sodium losses. We hypothesized that the kidney compensates for these losses by increasing the abundances of key sodium and water transporters and channels. Using targeted proteomic analysis via immunoblotting of kidney homogenates, we examined comprehensive regulation of transport proteins. In three studies, streptozotocin (STZ; 65 mg/kg) or vehicle was administered intraperitoneally to male Sprague-Dawley rats. In study 2, to control for potential renal toxicity of STZ, one group of STZ-treated rats was intensively treated with insulin to control diabetes. In another group, the reversibility of DM and related changes was assessed by treating animals with insulin for the final 4 days. In study 3, we correlated blood glucose to transporter changes by treating animals with different doses of insulin. In study 1, STZ treatment resulted in significantly increased band densities for the type 3 sodium/hydrogen exchanger (NHE3), the thiazide-sensitive Na-Cl cotransporter (NCC), and epithelial sodium channel (ENaC) subunits , , and (85- and 70-kDa bands) to 204, 125, 176, 132, 147, and 241% of vehicle mean, respectively. In study 2, aquaporin-2 (AQP2) and AQP3 were increased with DM, but not AQP1 or AQP4. Neither these changes, nor blood glucose itself, could be returned to normal by short-term intensive insulin treatment. Whole kidney abundance of AQP3, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), and -ENaC (85-kDa band) correlated most strongly with blood glucose in study 3. These comprehensive changes would be expected to decrease volume contraction accompanying large-solute and water losses associated with DM.

kidney; epithelial sodium channel; natriuresis; diuresis; type 2 sodium-phosphate cotransporter; type 3 sodium/hydrogen exchanger; bumetanide-sensitive sodium-potassium-2chloride cotransporter; aquaporin; sodium-chloride cotransporter; hyperglycemia; proteomics

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