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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
Author(s) -
Nickerson Andrew J.,
Rajendran Vazhaikkurichi M.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100203r
Subject(s) - aldosterone , secretion , medicine , endocrinology , cotransporter , crypt , bumetanide , apical membrane , chemistry , biology , biochemistry , membrane , sodium , organic chemistry
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.