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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/F1222    most recent 00604.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Madala Halagappa, V. K. Articles by Ecelbarger, C. M. Search for Related Content PubMed PubMed Citation Articles by Madala Halagappa, V. K. Articles by Ecelbarger, C. M.

Chronic candesartan alters expression and activity of NKCC2, NCC, and ENaC in the obese Zucker rat

Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, District of Columbia

Submitted 20 December 2007 ; accepted in final form 25 February 2008

The obese Zucker rat reportedly has increased activity of the intrarenal renin-angiotensin-aldosterone system, which conceptually could contribute to elevated salt sensitivity and blood pressure (BP). Our aim was to determine whether there was increased angiotensin II type 1 receptor (AT₁R)-mediated upregulation of expression or activity of the bumetanide-sensitive Na-K-2Cl cotransporter, the thiazide-sensitive Na-Cl cotransporter (NCC), and/or the epithelial sodium channel (ENaC) in obese vs. lean Zucker rats. Male obese and lean Zucker rats (10-wk old) were fed either 1) control chow (1% NaCl) or 2) chow with candesartan (CAN), an AT₁R antagonist (25 mg/kg·diet) for 14 wk (n = 8/treatment/body type). BP measured by radiotelemetry, was markedly reduced by CAN (20–25 mmHg) in both lean and obese rats with no body-type differences. Obese rats had significantly greater net natriuretic response to single injections of hydrochlorothiazide and benzamil, suggesting increased activity of NCC and ENaC, respectively; however, only the response to benzamil was reduced by CAN. CAN led to a significant reduction in whole kidney levels of NCC and -ENaC (70-kDa band) in both lean and obese rats. However, it significantly increased -ENaC and Na-K-2Cl cotransporter levels, and these increases were greater in obese rats. These studies suggest that relatively increased ENaC, but not NCC activity, in obese rats is due to enhanced AT₁R activity. CAN attenuated the reduction of several renal transporters in the obese rat kidney. Finally, differences in intrarenal AT₁R activity do not seem directly responsible for BP differences between lean and obese rats.

insulin resistance; type 2 diabetes; thiazide-sensitive Na-Cl cotransporter; bumetanide-sensitive Na-K-2Cl cotransporter