title: ENaC Dysregulation Through Activation of MEK1/2 Contributes to Impaired Na+ Absorption in Lymphocytic Colitis.
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 γ-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 TNFα, IFNγ, 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 TNFα, IFNγ, and IL-15 inhibited γ-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.
authors.affiliation: *Institute of Clinical Physiology, Charité-Campus Benjamin Franklin, Berlin, Germany; †Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Campus Benjamin Franklin, Berlin, Germany; ‡Institute of Pathology, Charité-Campus Benjamin Franklin, Berlin, Germany; §Max Planck Institute for Molecular Genetics, Berlin, Germany; and ‖Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Barmeyer
authors.forename: Irene
authors.initials: I
authors.lastname: Erko
authors.forename: Anja
authors.initials: A
authors.lastname: Fromm
authors.forename: Christian
authors.initials: C
authors.lastname: Bojarski
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Petra
authors.initials: P
authors.lastname: Dames
authors.forename: Martin
authors.initials: M
authors.lastname: Kerick
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.forename: Michal R
authors.initials: MR
authors.lastname: Schweiger
authors.forename: Jörg-Dieter
authors.initials: JD
authors.lastname: Schulzke
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D046730:Colitis, Lymphocytic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058266:Dielectric Spectroscopy; D017097:Electric Impedance; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D053503:Epithelial Sodium Channels; D014409:Tumor Necrosis Factor-alpha; D012964:Sodium; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human