Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Barmeyer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Erko, Irene UNSPECIFIED UNSPECIFIED UNSPECIFIED Fromm, Anja UNSPECIFIED orcid.org/0000-0003-4091-9612 UNSPECIFIED Bojarski, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Loddenkemper, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Dames, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Kerick, Martin UNSPECIFIED orcid.org/0000-0002-6298-4514 UNSPECIFIED Siegmund, Britta UNSPECIFIED orcid.org/0000-0002-0055-958X UNSPECIFIED Fromm, Michael UNSPECIFIED orcid.org/0000-0003-4497-7983 UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulzke, Joerg-Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language EPITHELIAL SODIUM-CHANNEL; MUCOSAL CYTOKINE PROFILE; MICROSCOPIC COLITIS; COLLAGENOUS COLITIS; CROHNS-DISEASE; USSING CHAMBER; ALPHA-SUBUNIT; ION-TRANSPORT; DISTAL COLON; EXPRESSION Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28315