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ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice
  1. Lin-Yan Huang1,2,
  2. Qing He3,
  3. Si-Jia Liang1,
  4. Ying-Xue Su1,
  5. Li-Xiong Xiong1,
  6. Qian-Qian Wu1,
  7. Qin-Yan Wu3,
  8. Jing Tao1,
  9. Jian-Ping Wang4,
  10. Yong-Bo Tang1,
  11. Xiao-Fei Lv1,
  12. Jie Liu1,
  13. Yong-Yuan Guan1,
  14. Rui-Ping Pang5,
  15. Jia-Guo Zhou1
  1. 1Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China
  2. 2School of Medical Technology, Xuzhou Medical College, Xuzhou, Jiagsu, China
  3. 3Gastrointestinal Institute, the 6th Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
  4. 4Department of Colorectal Surgery, The 6th Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
  5. 5Department of Physiology, Zhongshan School of Medcine, Sun Yat-Sen University, Guangzhou, Guangdong, China
  1. Correspondence to Professor Jia-Guo Zhou, Department of Pharmacology, Zhongshan School of Medcine, Sun Yat-Sen University, 74 Zhongshan 2 Rd, Guangzhou, Guangdong 510080, China; zhoujg{at}mail.sysu.edu.cn and Rui-Ping Pang, Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2 Rd, Guangzhou, Guangdong, 510080,China; pangruip{at}mail.sysu.edu.cn

Abstract

Background ClC-3 channel/antiporter plays a critical role in a variety of cellular activities. ClC-3 has been detected in the ileum and colon.

Objective To determine the functions of ClC-3 in the gastrointestinal tract.

Design After administration of dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), intestines from ClC-3−/− and wild-type mice were examined by histological, cellular, molecular and biochemical approaches. ClC-3 expression was determined by western blot and immunostaining.

Results ClC-3 expression was reduced in intestinal tissues from patients with UC or Crohn's disease and from mice treated with DSS. Genetic deletion of ClC-3 increased the susceptibility of mice to DSS- or TNBS-induced experimental colitis and prevented intestinal recovery. ClC-3 deficiency promoted DSS-induced apoptosis of intestinal epithelial cells through the mitochondria pathway. ClC-3 interacts with voltage-dependent anion channel 1, a key player in regulation of mitochondria cytochrome c release, but DSS treatment decreased this interaction. In addition, lack of ClC-3 reduced the numbers of Paneth cells and impaired the expression of antimicrobial peptides. These alterations led to dysfunction of the epithelial barrier and invasion of commensal bacteria into the mucosa.

Conclusions A defect in ClC-3 may contribute to the pathogenesis of IBD by promoting intestinal epithelial cell apoptosis and Paneth cell loss, suggesting that modulation of ClC-3 expression might be a new strategy for the treatment of IBD.

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