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02-01-2012 | General practice | Article

Tight junction disruption may drive inflammation in CKD


Free abstract

MedWire News: Chronic kidney disease (CKD) leads to disintegration of the intestinal epithelial tight junction, which in turn contributes to systemic inflammation, animal research suggests.

The findings, from a study in rats, offer insights into the "relentless inflammation" seen in CKD, which has "devastating effects on the cardiovascular system and other parts of the body," according to Nosratola Vaziri (University of California, Irvine, USA) in a press statement accompanying the study's publication.

Vaziri's team designed a study to test the hypothesis that impaired intestinal barrier function in uremia is due to disruption of the intestinal tight junction complex.

"Under normal conditions, the intestinal epithelial tight junction prevents paracellular penetration of bacteria and their toxic byproducts, digestive enzymes, and degraded food material," explain the researchers.

"However, in certain pathological conditions… the intestinal tight junction barrier is impaired allowing permeation of luminal antigens and proinflammatory products into the underlying intestinal tissue."

To investigate, the team induced CKD in Sprague-Dawley rats by one of two methods: surgery (partial nephrectomy) or feeding with an adenine-enriched diet. Rats that underwent sham surgery or ate a normal regular diet served as controls.

All rats were observed for 8 weeks. During this time, rats with CKD developed elevated levels of plasma urea and creatinine, reduced creatinine clearage, thickening of the colonic wall, and heavy infiltration of mononuclear leukocytes in the lamina propria.

Molecular analysis of the colonic epithelium revealed marked reductions in the expression of key tight junction transmembrane proteins (claudin-1, occludin, and zonula occludens-1) in both models of CKD as compared with controls.

This observation "elucidates the molecular mechanisms of the uremia-induced impairment of intestinal barrier function… and its contribution to the systemic inflammation and common occurrence of endotoxemia in advanced CKD," the authors remark.

By contrast, levels of messenger RNA of these three proteins 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," say Vaziri et al.

Writing in the journal Nephrology Dialysis Transplantation, the researchers conclude that uremia causes disintegration of the colonic tight junction apparatus, a phenomenon that contributes to the systemic inflammation and accounts for the previously demonstrated evidence of defective intestinal barrier function in humans and animals with advanced CKD.

"Further studies are planned to explore the effect of uremia in other segments of the gastrointestinal tract," they add.

By Joanna Lyford

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