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

Abstract

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 (AT(1)R)-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 AT(1)R antagonist (25 mg/kg.diet) for 14 wk (n = 8/treatment/body type). BP measured by radiotelemetry, was markedly reduced by CAN ( approximately 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 gamma-ENaC (70-kDa band) in both lean and obese rats. However, it significantly increased alpha-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 AT(1)R activity. CAN attenuated the reduction of several renal transporters in the obese rat kidney. Finally, differences in intrarenal AT(1)R activity do not seem directly responsible for BP differences between lean and obese rats.

Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK

“…Similar to previous studies (1,28,39), expression levels of the ENaC subunits did not change in synchrony with one another. Levels of ␤-ENaC were reduced in the kidneys of HFD-fed mice, whereas expression of the other subunits was unchanged.…”

“…The natriuretic response to furosemide has been used by others as a marker of the in vivo activity of NKCC2 (18,28,38,40). Mice (14 wk old) were administered intraperitoneal injections of 16.5 mg/kg furosemide (Sigma-Aldrich).…”

“…Studies examining the effects of obesity on the abundance of renal Na ϩ transporters have predominantly used lean Zucker and ZO rats (1,20,21,28,38,39). ZO rats have a mutation of the leptin receptor and profound hyperinsulinaemia.…”

Some Assembly Required: Putting the Epithelial Sodium Channel Together

“…Since our initial review of this subject, multiple examples of non-coordinate regulation of ENaC subunit protein or message have continued to appear in the literature (22,23,(52)(53)(54). It seems likely that more than one mechanism is required to fully explain this phenomenon.…”

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

“…We have clearly shown that chronic blockade of the angiotensin II (ANG II) type 1 receptor (AT1R) reduces blood pressure in both lean and obese Zucker rats (30). However, the effect of AT1R blockade on dopamine receptor regulation in these rats has not been tested.…”