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Aldosterone up-regulates basolateral Na⁺ -K⁺ -2Cl^- cotransporter-1 to support enhanced large-conductance K⁺ channel-mediated K⁺ secretion in rat distal colon.

ABSTRACT: Na⁺ -K⁺ -2Cl^- cotransporter-1 (NKCC1) facilitates basolateral K⁺ and Cl^- uptake, supporting their efflux across mucosal membranes of colonic epithelial cells. NKCC1 activity has also been shown to be critical for electrogenic K⁺ secretion induced by aldosterone, which is known to stimulate large-conductance K⁺ (BK) channel expression in mucosal membranes. This study was aimed to (1) identify whether aldosterone enhances NKCC1 expression specifically to support BK-mediated K⁺ secretion and (2) to determine whether increased NKCC1 supports electrogenic Cl^- secretion in parallel to K⁺ secretion. Dietary Na⁺ depletion was used to induce secondary hyperaldosteronism in rats, or aldosterone was administered ex vivo to rat distal colonic mucosae. NKCC1-dependent electrogenic K⁺ or Cl^- secretion was measured as a function of short circuit current (I_SC ). qRT-PCR, western blot, and immunofluorescence analyses were performed using standard techniques. Aldosterone enhanced NKCC1 and BKα expression and electrogenic K⁺ secretion in the distal colon, which was inhibited by either serosal bumetanide (NKCC1 inhibitor) or mucosal iberiotoxin (IbTX; BK channel blocker), but not TRAM-34 (IK channel blocker). Expression of NKCC1 and BKα proteins was enhanced in crypt cells of hyper-aldosterone rats. However, neither NKCC1-dependent Cl^- secretion nor CFTR (apical Cl^- channel) expression was enhanced by aldosterone. We conclude that aldosterone enhances NKCC1 to support BK-mediated K⁺ secretion independently of Cl^- secretion in the distal colon. The regulation of NKCC1 expression/K⁺ secretion by aldosterone may be a therapeutic target in treating gastrointestinal disorders associated with alterations in colonic K⁺ transport, such as colonic pseudo-obstruction, and hyperkalemia associated with renal disease.

SUBMITTER: Nickerson AJ

PROVIDER: S-EPMC9777186 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Aldosterone up-regulates basolateral Na+ -K+ -2Cl- cotransporter-1 to support enhanced large-conductance K+ channel-mediated K+ secretion in rat distal colon.

Nickerson Andrew J AJ Rajendran Vazhaikkurichi M VM

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20210501 5

Na+ -K+ -2Cl- cotransporter-1 (NKCC1) facilitates basolateral K+ and Cl- uptake, supporting their efflux across mucosal membranes of colonic epithelial cells. NKCC1 activity has also been shown to be critical for electrogenic K+ secretion induced by aldosterone, which is known to stimulate large-conductance K+ (BK) channel expression in mucosal membranes. This study was aimed to (1) identify whether aldosterone enhances ...[more]

PMID: 33908679

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Project description:Primary hyperaldosteronism (PA) is characterized by aldosterone excess and hypertension. This may be linked to increased renal Na+ reabsorption via the epithelial Na+ channel (ENaC) and the NaCl cotransporter (NCC). The majority of PA patients have normal plasma K+ levels, but a subset of cases are associated with hypokalemia. High NCC levels observed in long-term studies with aldosterone-infused rodents have been attributed to direct effects of aldosterone. Aldosterone can also increase active phosphorylated NCC (pT58-NCC) acutely. However, direct effects of aldosterone on NCC have been contested by recent studies indicating that it is rather an indirect effect of hypokalemia. We therefore set out to determine isolated long-term aldosterone and K+ effects on ENaC and NCC using various in vivo and ex vivo approaches. In mice, aldosterone-induced hypokalemia was prevented by simultaneous amiloride infusion, coupled to increased cleavage of α- and γENaC but no effect on NCC. Regression analyses of in vivo data showed a positive correlation between aldosterone/K+ and αENaC but a negative correlation with NCC and pT58-NCC. Ex vivo, exposure of kidney tubules for 21 h to aldosterone increased cleavage of αENaC and γENaC, but no effects were observed on NCC or pT58-NCC. Exposure of tubules to low K+ media reduced αENaC but increased NCC and pT58-NCC. As hypokalemia can enhance cell proliferation markers in the distal convoluted tubule (DCT), we hypothesized that aldosterone infusion would increase proliferating cell nuclear antigen (PCNA) expression. Infusion of aldosterone in mice for 6 days greatly increased PCNA expression in the DCT. Collectively, in vivo and ex vivo data suggest that both aldosterone and K+ can increase ENaC directly. In contrast, the observed increase in abundance and phosphorylation of NCC in aldosterone-infused mice is likely an indirect effect of enhanced ENaC-mediated K+ secretion and subsequent hypokalemia. Thus, it is possible that NCC may only be increased in PA when the condition is associated with hypokalemia.

Dataset Information

Aldosterone up-regulates basolateral Na⁺ -K⁺ -2Cl^- cotransporter-1 to support enhanced large-conductance K⁺ channel-mediated K⁺ secretion in rat distal colon.

Publications

Aldosterone up-regulates basolateral Na<sup>+</sup> -K<sup>+</sup> -2Cl<sup>-</sup> cotransporter-1 to support enhanced large-conductance K<sup>+</sup> channel-mediated K<sup>+</sup> secretion in rat distal colon.

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