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

VK Madala Halagappa, S Tiwari… - American Journal …, 2008 - journals.physiology.org
VK Madala Halagappa, S Tiwari, S Riazi, X Hu, CM Ecelbarger
American Journal of Physiology-Renal Physiology, 2008journals.physiology.org
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 …
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 γ-ENaC (70-kDa band) in both lean and obese rats. However, it significantly increased α-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.
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