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

Abstract

Background Gut inflammation is prevalent in chronic kidney disease (CKD) and likely contributes to systemic inflammation via disruption of the epithelial tight junction with subsequent endotoxin and bacterial translocation. Aims To study the expression profile of inflammatory and tight junction proteins in the colon from CKD rats compared to healthy controls, and demonstrate the role of Nrf2 (transcription factor nuclear factor erythroid 2-related factor 2) using a potent Nrf2 activator. Methods CKD was induced via 5/6 nephrectomy in Sprague-Dawley rats, and dh404 (2 mg/kg/day) was used to study the effects of systemic Nrf2 activation. The experimental groups included sham, CKD and CKD? dh404 rats. Blood and colon tissues were analyzed after a 10-week study period. Results Colon from CKD rats showed histological evidence of colitis, depletion of epithelial tight junction proteins, significant reduction of Nrf2 and its measured target gene products (NQO1, catalase, and CuZn SOD), activation of NFkB, and upregulation of pro-inflammatory molecules (COX-2, MCP-1, iNOS, and gp91 phox ). Treatment with dh404 attenuated colonic inflammation, restored Nrf2 activity and levels of NQO1, catalase and CuZn SOD, decreased NFkB and lowered expression of COX-2, MCP-1, iNOS, and gp91 phox . This was associated with restoration of colonic epithelial tight junction proteins (occludin and claudin-1). Conclusions CKD rats exhibited colitis, disruption of colonic epithelial tight junction, activation of inflammatory mediators, and impairment of Nrf2 pathway. Treatment with an Nrf2 activator restored Nrf2 activity, attenuated colonic inflammation, and restored epithelial tight junction proteins.

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

“…The apical junctional complex is composed of transmembrane proteins including claudins (a group of at least 20 tissue-specific proteins), occludin, E-cadherin, and cytoplasmic linker proteins such as zonula occludens [49]. Rodent studies have confirmed that CKD is associated with depletion of gut epithelial tight junction proteins including occludin and claudin-1 [50,51] and deficiency of the antioxidant transcription factor Nrf2 [52]. This leaky barrier allows translocation of gut-derived bacterial DNA and uremic toxins into the bloodstream of CKD patients [43,[53][54][55][56][57].…”

Berberine Reduces Uremia-Associated Intestinal Mucosal Barrier Damage

“…In addition, intestinal inflammation has been considered as an important indicator for the intestinal mucosal barrier function changes. 8,30,31) An increase in intestinal inflammation has a positive correlation with the severity of intestinal mucosal barrier damage. In the present study, berberine treatment significantly reduced the intestinal mucosal and submucosal inflammation in histopathological observation, and the MPO activity, a sensitive index to evaluate the extent of inflammatory response in various inflammatory disease, was also significantly decreased by berberine treatment.…”

The cross-talk between the kidney and the gut: implications for chronic kidney disease

“…Indeed, in uremic rats, disruptions in tight junctions were associated with local inflammation in the gastrointestinal tissue [6,67]. It has been proposed that the impaired nuclear factorerythroid-2-related factor 2 (Nrf2) system is involved in uremia-associated intestinal inflammation and breakdown of intestinal epithelial tight junctions [68]. Nrf2 is a transcription factor that activates genes encoding antioxidant and phase II detoxifying enzymes and related proteins.…”

“…This nuclear factor plays a central role in cellular defense against oxidative stress [69,70]. The contribution of the impaired Nrf2 system to CKD-induced damage to the intestinal barrier was demonstrated when Lau et al [68], using a potent Nrf2 activator, observed attenuation of colonic inflammation and restoration of epithelial tight junction proteins in the colon of CKD rats.…”