TY - JOUR
T1 - Na-H exchanger isoform-2 (NHE2) mediates butyrate-dependent Na+ absorption in dextran sulfate sodium (DSS)-induced Colitis
AU - Rajendran, Vazhaikkurichi M.
AU - Kumar, Navalpur S.Nanda
AU - Tse, Chung M.
AU - Binder, Henry J.
N1 - Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015/10/16
Y1 - 2015/10/16
N2 - Diarrhea associated with ulcerative colitis (UC) occurs primarily as a result of reduced Na+ absorption. Although colonic Na+ absorption is mediated by both epithelial Na+ channels (ENaC) and Na-H exchangers (NHE), inhibition of NHE-mediated Na+ absorption is the primary cause of diarrhea in UC. As there are conflicting observations reported on NHE expression in human UC, the present study was initiated to identify whether NHE isoforms (NHE2 and NHE3) expression is altered and how Na+ absorption is regulated in DSS-induced inflammation in rat colon, a model that has been used to study UC. Western blot analyses indicate that neither NHE2 nor NHE3 expression is altered in apical membranes of inflamed colon. Na+ fluxes measured in vitro under voltage clamp conditions in controls demonstrate that both HCO3--dependent and butyrate-dependent Na+ absorption are inhibited by S3226 (NHE3-inhibitor), but not by HOE694 (NHE2-inhibitor) in normal animals. In contrast, in DSS-induced inflammation, butyrate-, but not HCO3--dependent Na+ absorption is present and is inhibited by HOE694, but not by S3226. These observations indicate that in normal colon NHE3 mediates both HCO3--dependent and butyrate-dependent Na+ absorption, whereas DSS-induced inflammation activates NHE2, which mediates butyrate-dependent (but not HCO3--dependent) Na+ absorption. In in vivo loop studies HCO3--Ringer and butyrate-Ringer exhibit similar rates of water absorption in normal rats, whereas in DSS-induced inflammation luminal butyrate-Ringer reversed water secretion observed with HCO3--Ringer to fluid absorption. Lumen butyrate-Ringer incubation activated NHE3-mediated Na+ absorption in DSS-induced colitis. These observations suggest that the butyrate activation of NHE2 would be a potential target to control UC-associated diarrhea.
AB - Diarrhea associated with ulcerative colitis (UC) occurs primarily as a result of reduced Na+ absorption. Although colonic Na+ absorption is mediated by both epithelial Na+ channels (ENaC) and Na-H exchangers (NHE), inhibition of NHE-mediated Na+ absorption is the primary cause of diarrhea in UC. As there are conflicting observations reported on NHE expression in human UC, the present study was initiated to identify whether NHE isoforms (NHE2 and NHE3) expression is altered and how Na+ absorption is regulated in DSS-induced inflammation in rat colon, a model that has been used to study UC. Western blot analyses indicate that neither NHE2 nor NHE3 expression is altered in apical membranes of inflamed colon. Na+ fluxes measured in vitro under voltage clamp conditions in controls demonstrate that both HCO3--dependent and butyrate-dependent Na+ absorption are inhibited by S3226 (NHE3-inhibitor), but not by HOE694 (NHE2-inhibitor) in normal animals. In contrast, in DSS-induced inflammation, butyrate-, but not HCO3--dependent Na+ absorption is present and is inhibited by HOE694, but not by S3226. These observations indicate that in normal colon NHE3 mediates both HCO3--dependent and butyrate-dependent Na+ absorption, whereas DSS-induced inflammation activates NHE2, which mediates butyrate-dependent (but not HCO3--dependent) Na+ absorption. In in vivo loop studies HCO3--Ringer and butyrate-Ringer exhibit similar rates of water absorption in normal rats, whereas in DSS-induced inflammation luminal butyrate-Ringer reversed water secretion observed with HCO3--Ringer to fluid absorption. Lumen butyrate-Ringer incubation activated NHE3-mediated Na+ absorption in DSS-induced colitis. These observations suggest that the butyrate activation of NHE2 would be a potential target to control UC-associated diarrhea.
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U2 - 10.1074/jbc.M115.654277
DO - 10.1074/jbc.M115.654277
M3 - Article
C2 - 26350456
AN - SCOPUS:84944463790
SN - 0021-9258
VL - 290
SP - 25487
EP - 25496
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 42
ER -