Antisecretory effects of neuropeptide Y in the mouse colon are region-specific and are lost in DSS-induced colitis

Abstract

Regulation of water movement in the gut is an important homeostatic event that is critical to normal intestinal function. We assessed the effect of neuropeptide Y (NPY) on epithelial ion transport in the normal and inflamed mouse colons. Colitis was induced by dextran sodium sulfate (DSS, 4% wt./vol.) administered in the drinking water for 5 days followed by 3 days of regular water. Segments of proximal and distal colons were excised and short-circuit current (I SC) was measured in Ussing chambers to assess net electrogenic active ion transport. NPY Y 1 receptor (Y 1R) expression was measured by quantitative real-time PCR and immunohistochemistry. Challenge of distal colon from normal mice with NPY (10 − 7 M) evoked a drop in I SC (51.4 ± 9.1 μA/cm 2), which was dependent on Cl − flux, was insensitive to neural blockade with tetrodotoxin and was mediated primarily through the Y 1R. In contrast, the proximal colon was largely unresponsive to NPY, expressing ∼ ten-fold less Y 1R mRNA compared to the distal colon. These findings confirm that specific regional regulation of ion transport occurs in the colon. Segments of proximal and distal colons from mice with DDS-induced colitis were virtually unresponsive to NPY, expressed less Y 1R mRNA than tissues from control mice and displayed loss of Y 1R protein expression in the colonic epithelium. This hypo-responsiveness to an antisecretory stimulus adds to the well-documented loss of responsiveness to prosecretory agents during inflammation, attesting to a profound loss of control of active ion transport during enteric inflammatory disease.