Decreased expression of apical Na⁺ channels and basolateral Na⁺, K⁺‐ATPase in ulcerative colitis

Abstract

Impaired absorption of sodium (Na+) and water is a major factor in the pathogenesis of diarrhoea in ulcerative colitis (UC). Electrogenic Na+ absorption, present mainly in human distal colon and rectum, is defective in UC, but the molecular basis for this is unclear. The effect of UC on the expression of apical Na+ channels (ENaC) and basolateral Na+, K+-ATPase, the critical determinants of electrogenic Na+ transport, was therefore investigated in this study. Sigmoid colonic and/or proximal rectal mucosal biopsies were obtained from patients with mild to moderate UC, and patients with functional abdominal pain (controls). ENaC subunit expression was studied by immunohistochemistry, western blot analysis, and in situ hybridization, and Na+, K+-ATPase isoform expression was studied by immunohistochemistry, western blotting, and northern blot analysis. UC was associated with substantial decreases in the expression of the ENaC beta- and gamma-subunit proteins and mRNAs, whereas the decrease in ENaC alpha-subunit protein detected by immunolocalization was less marked. The levels of expression of Na+, K+-ATPase alpha1- and beta1-isoform proteins were also lower in UC patients than in controls, although there were no differences in Na+, K+-ATPase alpha1- and beta1-isoform mRNA levels between the two groups. Taken together, these results show that UC results mainly in decreased expression of the apical ENaC beta- and gamma-subunits, as well as the basolateral Na+, K+-ATPase alpha1- and beta1-isoforms. In conclusion, these changes provide a basis for the low/negligible levels of electrogenic Na+ absorption seen in the distal colon and rectum of UC patients, which contribute to the pathogenesis of diarrhoea in this disease.

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

“…Depending on their concentrations within the colonic lumen, BA can have, via FXR signaling, not only a prosecretory but also an anitsecretory effect (Keating et al, 2009). Intraluminal BA in moderate quantities can prevent fluid accumulation in the intestine by inhibition of the Na + channel and K + -ATPase expression (Mroz et al, 2013); expression of both transporters was described as decreased in UC colitis (Greig et al, 2004;Sullivan et al, 2009). Our studies in adolescent IBD reveal low ileal FGF-19 levels in CD and UC.…”

Role of epithelial ion transports in inflammatory bowel disease

“…ϩ Channels' Activity Is Decreased in IBD ENaC-mediated sodium transport, most important in the distal colon and rectum, is impaired in both IBD-afflicted colon (43,49,50,115) and experimental colitis models (JAK3 Ϫ/Ϫ or IL-2 Ϫ/Ϫ mice) (13, 14, 139) (see Table 5). TNF-␣ and IFN-␥ are once more involved in this downregulation: they both reduce ␤-and ␥-subunit ENaC gene expressions in UC (5), and TNF-␣ reduces ␥-subunit transcription even in macroscopically noninflamed colon in CD (161).…”

Mechanisms of ENaC Regulation and Clinical Implications

“…Decreased expression of ENaC subunits in human biopsy samples from patients with colitis is a mechanism, but further studies are warranted. 147,148 Lung. The importance of ENaC in the regulation of airway surface liquid volume is suggested by the finding that loss-offunction mutations in PHA-I are associated with neonatal respiratory distress syndrome.…”