title: Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation.
abstract: BACKGROUND
  Inflammation is a constant feature and a major mediator of the progression of chronic kidney disease (CKD) and its numerous complications. There is increasing evidence pointing to the impairment of intestinal barrier function and its contribution to the prevailing inflammation in advanced CKD. Under normal condition, the intestinal epithelium and its apical tight junction prevent entry of the luminal microorganisms, harmful microbial by-products and other noxious contents in the host's internal milieu. This study was designed to test the hypothesis that impaired intestinal barrier function in uremia must be due to disruption of the intestinal tight junction complex.
  
  
  METHODS
  Sprague-Dawley (SD) rats were randomized to undergo 5/6 nephrectomy (CKD) or sham-operation (control) and observed for 8 weeks. In a separate experiment, SD rats were rendered uremic by addition of 0.7% adenine to their food for 2 weeks and observed for an additional 2 weeks. Rats consuming a regular diet served as controls. The animals were then euthanized and their colons were removed and processed for expression of the key constituents of the tight junction complex using real-time polymerase chain reaction, western blot analysis and immunohistological examinations.
  
  
  RESULTS
  The CKD groups showed elevated plasma urea and creatinine, reduced creatinine clearance, thickened colonic wall and heavy infiltration of mononuclear leukocytes in the lamina propria. This was associated with marked reductions in protein expressions of claudin-1 (70-90%), occludin (50-70%) and ZO-1 (80-90%) in the colonic mucosa in both CKD models compared with the corresponding controls. The reduction in the abundance of the given proteins was confirmed by immunohistological examinations. In contrast, messenger RNA abundance of occludin, claudin-1 and ZO-1 was either unchanged or elevated pointing to the post-transcriptional/post-translational modification as a cause of the observed depletion of the tight junction proteins.
  
  
  CONCLUSIONS
  The study revealed, for the first time, that uremia results in depletion of the key protein constituents of the colonic tight junction, a phenomenon which can account for the impaired intestinal barrier function and contribute to the systemic inflammation in CKD.
authors: Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, CA, USA. ndvaziri@uci.edu
authors: Nosratola D
authors: ND
authors: Vaziri
authors: Jun
authors: J
authors: Yuan
authors: Ardeshir
authors: A
authors: Rahimi
authors: Zhenmin
authors: Z
authors: Ni
authors: Hyder
authors: H
authors: Said
authors: Veedamali S
authors: VS
authors: Subramanian
mesh_terms: D000818:Animals; D015153:Blotting, Western; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism*; D014511:Uremia / Q000150:complications / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D062445:Claudin-1; D062793:Occludin; D012333:RNA, Messenger; D062725:Tight Junction Proteins; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein