Barmeyer, Christian, Erko, Irene, Fromm, Anja ORCID: 0000-0003-4091-9612, Bojarski, Christian, Loddenkemper, Christoph, Dames, Petra, Kerick, Martin ORCID: 0000-0002-6298-4514, Siegmund, Britta ORCID: 0000-0002-0055-958X, Fromm, Michael ORCID: 0000-0003-4497-7983, Schweiger, Michal R. and Schulzke, Joerg-Dieter (2016). ENaC Dysregulation Through Activation of MEK1/2 Contributes to Impaired Na+ Absorption in Lymphocytic Colitis. Inflamm. Bowel Dis., 22 (3). S. 539 - 548. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1536-4844

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Abstract

Background: Lymphocytic colitis (LC) causes watery diarrhea. We aimed to identify mechanisms of altered Na+ absorption and regulatory inputs in patients with LC by examining the epithelial Na+ channel (ENaC) function as the predominant Na+ transport system in human distal colon. Methods: Epithelial Na+ channel function and regulation was analyzed in biopsies from sigmoid colon of patients with LC and in rat distal colon in Ussing chambers. ENaC-subunit expression was measured by real-time PCR and RNA sequencing. Correction factors for subepithelial resistance contributions were determined by impedance spectroscopy. Upstream regulators in LC were determined by RNA sequencing. Results: Epithelial Na+ channel-mediated electrogenic Na+ transport was inhibited despite aldosterone stimulation in human sigmoid colon of patients with LC. The increase in gamma-ENaC mRNA expression in response to aldosterone was MEK1/2-dependently reduced in LC, since it could be restored toward normal by MEK1/2 inhibition through U0126. Parallel experiments for identification of signaling in rat distal colon established MEK1/2 to be activated by a cytokine cocktail of TNF alpha, IFN gamma, and IL-15, which were identified as the most important regulators in the upstream regulator analysis in LC. Conclusions: In the sigmoid colon of patients with LC, the key effector cytokines TNF alpha, IFN gamma, and IL-15 inhibited gamma-ENaC upregulation in response to aldosterone through a MEK1/2-mediated pathway. This prevents ENaC to reach its maximum transport capacity and results in Na+ malabsorption which contributes to diarrhea.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Barmeyer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erko, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fromm, AnjaUNSPECIFIEDorcid.org/0000-0003-4091-9612UNSPECIFIED
Bojarski, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loddenkemper, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dames, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerick, MartinUNSPECIFIEDorcid.org/0000-0002-6298-4514UNSPECIFIED
Siegmund, BrittaUNSPECIFIEDorcid.org/0000-0002-0055-958XUNSPECIFIED
Fromm, MichaelUNSPECIFIEDorcid.org/0000-0003-4497-7983UNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulzke, Joerg-DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-283159
DOI: 10.1097/MIB.0000000000000646
Journal or Publication Title: Inflamm. Bowel Dis.
Volume: 22
Number: 3
Page Range: S. 539 - 548
Date: 2016
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1536-4844
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EPITHELIAL SODIUM-CHANNEL; MUCOSAL CYTOKINE PROFILE; MICROSCOPIC COLITIS; COLLAGENOUS COLITIS; CROHNS-DISEASE; USSING CHAMBER; ALPHA-SUBUNIT; ION-TRANSPORT; DISTAL COLON; EXPRESSIONMultiple languages
Gastroenterology & HepatologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28315

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