Chronic Kidney Disease Causes Disruption of Gastric and Small Intestinal Epithelial Tight Junction

Abstract

Background: Integrity of the tight junction (TJ) which seals the gap between the epithelial cells of the gastrointestinal tract is critical in preventing the entry of the microbial toxins, antigens, and other harmful products in the subepithelial tissues and the internal milieu. By enabling the absorption of these products, impairment of the intestinal epithelial barrier leads to local and systemic inflammation. We have recently found depletion of the key protein constituents of colonic epithelial TJ in animals with chronic kidney disease (CKD). Postmortem studies have revealed the presence of inflammation throughout the gastrointestinal tract in uremic humans. This observation suggests that uremia may cause disruption of the epithelial barrier in all segments of the gastrointestinal tract including the stomach, jejunum, and ileum. The present study was undertaken to explore this possibility. Methods: Sprague-Dawley rats were randomized to CKD or control groups. The CKD group was subjected to 5/6 nephrectomy while the control group underwent a sham operation. The animals were observed for 10 weeks at which time they were euthanized and their stomachs, jejunums, and ileums were removed and processed for measurement of TJ proteins. Results: The CKD rats showed marked azotemia, systemic oxidative stress, and marked depletion of the key protein constituents of the epithelial TJ (claudin-1, occludin, and ZO1) in the stomach, jejunum, and ileum. Conclusions: The present study extends the earlier finding of uremia-induced disruption of colonic epithelial TJ by documenting the involvement of the stomach, jejunum, and ileum as well.

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

“…4. In confirmation of earlier studies [5,6], the key components of the tight junction apparatus, i.e., zona occludens-1 (ZO-1), occludin and claudin-1 were significantly depleted in the colons of untreated CKD group. We previously reported that mRNA levels of these proteins were unchanged or elevated in CKD, suggesting posttranscriptional modification [5].…”

“…Almost 30 years ago, Vaziri et al [4] showed the presence of inflammation throughout the gastrointestinal tract (including gastritis, enteritis, and colitis) in a postmortem analysis of 78 hemodialysis patients. Recent studies by our group have demonstrated disruption of the epithelial tight junction throughout the gastrointestinal tract and its association with endotoxemia, local and systemic inflammation, and oxidative stress in animal models of CKD [5][6][7]. Subsequent in vitro studies revealed the role of urea and its conversion to ammonia and ammonium hydroxide as a main cause of the breakdown of the gut epithelial tight junction [8,9].…”

Inflammation: A Key Contributor to the Genesis and Progression of Chronic Kidney Disease

“…Consequently, slowing of the gut transit and constipation are common, which favor a dominant growth of proteolytic bacteria (fermenting proteins) over saccharolytic bacteria (fermenting carbohydrates) [51] . Proteolytic bacteria generate toxic metabolites and ammonia that disrupt the intestinal mucosal barrier [52,53] . Moreover, CKD patients tend to have varying degrees of uremic toxin accumulation including urea and often uric acid, which, after entering the intestinal tract, can induce growth of urease and uricase, producing bacteria [54,55] .…”

Role of Altered Intestinal Microbiota in Systemic Inflammation and Cardiovascular Disease in Chronic Kidney Disease

“…Uremia results in the impairment of the intestinal epithelial barrier structure and function, which plays a major part in the pathogenesis of systemic inflammation [7,54]. As described below, emerging evidence points to the role of urea as a major mediator of the intestinal epithelial barrier dysfunction and resultant systemic inflammation.…”