Altered Expression of Ion Transporters Contributes to the Pathogenesis of Acute Ulcerative Colitis: Selective Anti-Inflammatory Effects of Nobiletin

Background: We investigated the roles and regulation of contractile and sodium ion transporter proteins in the pathogenesis of diarrhea in acute ulcerative colitis. Methods: Acute ulcerative colitis was induced in male Sprague-Dawley rats using dextran sulfate sodium (DSS) in drinking water for seven days. The effects of nobiletin, a citrus flavonoid, were also examined. Results: Increased myeloperoxidase activity, colon mass, and inflammatory cell infiltration associated with damage to goblet cells and the epithelial cell lining indicated the development of acute ulcerative colitis. SERCA-2 calcium pump expression remained unchanged, whereas the phospholamban (PLN) regulatory peptide was reduced and its phosphorylated form (PLN-P) increased, suggesting a post-translational enhancement of SERCA-2 activity in the inflamed colon. Higher levels of IP3 were associated with a decrease in the Gαq protein levels without altering phospholipase C expression, suggesting that IP3 regulation is independent of Gαq protein signaling. In addition, the expression of sodium/hydrogen exchanger isoforms NHE-1, NHE-3 and carbonic anhydrase-1 and sodium pump activity were decreased in the inflamed colon. Nobiletin treatment of colitis selectively reversed the inflammatory and oxidative stress markers, including superoxide dismutase and catalase without restoring the expression of ion transporters. Conclusions: This study highlights alterations in the expression of ion transporters and their regulatory proteins in acute ulcerative colitis. These changes in the ion transporters are likely to reduce NaCl absorption and alter contractility, thereby contributing to the pathogenesis of diarrhea in the present acute model of ulcerative colitis. Nobiletin selectively ameliorates acute colitis in this model.