Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease.
Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease.
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DOI：
10.1159/000345969
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发表时间：
2013
影响因子：
4.2
通讯作者：
Norris K
中科院分区：
文献类型：
--
作者：
Vaziri ND;Yuan J;Norris K
慢性肾脏疾病（CKD）损害肠道屏障功能，导致内毒素血症和全身炎症。我们发现CKD动物的肠上皮紧密连接（TJ）蛋白缺失。我们进一步表明，在培养基中加入ESRD患者的血浆会引起培养的人肠细胞中跨上皮电阻（TER）的显著下降和TJ蛋白的耗竭。血液透析后血浆中的这些效应的严重程度低于血液透析前血浆，表明可透析剂的作用。本研究验证了尿毒症患者肠屏障功能障碍可能是由于尿素扩散到肠道并通过微生物尿素酶转化为氨的假设。将人肠细胞（T84细胞）接种在Transwell板上，并在TER超过1，000 Ω. cm 2时使用，以确保完全极化和TJ形成。然后将汇合的细胞在含有0、42或74 mg/dl尿素或尿素加脲酶的培养基中孵育24小时以模拟微生物植物群的存在。在临床相关浓度下，尿素导致TER和关键TJ蛋白（cluadin-1、occludin和ZO 1）浓度依赖性下降。尿素的作用被尿素酶显著放大，导致细胞脱离、TER消散和TJ蛋白大量丢失。尿毒症诱导的肠TJ和屏障功能的破坏部分地由尿素介导，尿素通常被认为是无毒的保留代谢物。这些发现揭示了降低尿素策略的有益作用的新机制，例如低蛋白饮食和更长时间和更频繁的透析方案在晚期CKD中。
Chronic kidney disease (CKD) impairs intestinal barrier function which leads to endotoxemia and systemic inflammation. We have found depletion of intestinal epithelial tight junction (TJ) proteins in animals with CKD. We further showed that addition of ESRD patients' plasma to the culture medium provokes marked drop in transepithelial electrical resistance (TER) and depletion of TJ proteins in cultured human enterocytes. These effects were less severe with post- than pre-hemodialysis plasma suggesting the role of dialyzable agent(s). This study tested the hypothesis that intestinal barrier dysfunction in uremia may be due to diffusion of urea into the gut and its conversion to ammonia by microbial urease. Human enterocytes (T84 cells) were seeded on Transwell plates and utilized when TER exceeded 1,000 Ω.cm2 to ensure full polarization and TJ formation. Confluent cells were then incubated for 24 hr in media containing zero, 42, or 74 mg/dl urea or urea plus urease to simulate presence of microbial flora. At clinically-relevant concentrations, urea caused a concentration-dependent fall in TER and the key TJ protein; cluadin-1, occludin, and ZO1. The effects of urea were dramatically amplified by urease causing cells detachment, dissipation of TER, and massive loss of TJ proteins. uremia-induced disruption of intestinal TJ and barrier function is, in part, mediated by urea which is generally considered to be a nontoxic retained metabolite. These findings reveal a novel mechanism for salutary effect of urea-lowering strategies e.g. low protein diet and longer and more frequent dialysis regimens in advanced CKD.
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影响因子：
19.6
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