Role of Nrf2 dysfunction in uremia-associated intestinal inflammation and epithelial barrier disruption.
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.


OBJECTIVE
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.
Division of Nephrology and Hypertension, Department of Medicine, University of California-Irvine, C362 Medical Sciences I, Irvine, CA, 92697, USA, wllau@uci.edu.
Wei Ling
WL
Lau
Shu-Man
SM
Liu
Sogol
S
Pahlevan
Jun
J
Yuan
Mahyar
M
Khazaeli
Zhenmin
Z
Ni
Jefferson Y
JY
Chan
Nosratola D
ND
Vaziri
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003092:Colitis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000378:metabolism*; D009392:Nephrectomy; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D014511:Uremia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D062725:Tight Junction Proteins; C547749:dh404 compound; D009828:Oleanolic Acid