Dietary Na+ depletion up-regulates NKCC1 expression and enhances electrogenic Cl- secretion in rat proximal colon

Abstract

The corticosteroid hormone, aldosterone, markedly enhances K⁺ secretion throughout the colon, a mechanism critical to its role in maintaining overall K⁺ balance. Previous studies demonstrated that basolateral NKCC1 was up-regulated by aldosterone in the distal colon specifically to support K⁺ secretion-which is distinct from the more well-established role of NKCC1 in supporting luminal Cl^- secretion. However, considerable segmental variability exists between proximal and distal colonic ion transport processes, especially concerning their regulation by aldosterone. Furthermore, delineating such region-specific effects has important implications for the management of various gastrointestinal pathologies. Experiments were therefore designed to determine whether aldosterone similarly up-regulates NKCC1 in the proximal colon to support K⁺ secretion. Using dietary Na⁺ depletion as a model of secondary hyperaldosteronism in rats, we found that proximal colon NKCC1 expression was indeed enhanced in Na⁺-depleted (i.e., hyperaldosteronemic) rats. Surprisingly, electrogenic K⁺ secretion was not detectable by short-circuit current (I_SC) measurements in response to either basolateral bumetanide (NKCC1 inhibitor) or luminal Ba²⁺ (non-selective K⁺ channel blocker), despite enhanced K⁺ secretion in Na⁺-depleted rats, as measured by ⁸⁶Rb⁺ fluxes. Expression of BK and IK channels was also found to be unaltered by dietary Na⁺ depletion. However, bumetanide-sensitive basal and agonist-stimulated Cl^- secretion (I_SC) were significantly enhanced by Na⁺ depletion, as was CFTR Cl^- channel expression. These data suggest that NKCC1-dependent secretory pathways are differentially regulated by aldosterone in proximal and distal colon. Development of therapeutic strategies in treating pathologies related to aberrant colonic K⁺/Cl^- transport-such as pseudo-obstruction or ulcerative colitis-may benefit from these findings.

Keywords: Aldosterone; CFTR; Cl− secretion; Na+ depletion; Ussing chamber.