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

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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 gp91phox). 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 gp91phox. 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.

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Acknowledgments

This study was funded by an unrestricted research grant from Reata Pharmaceuticals. WLL was supported by a Sanofi renal fellowship award.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Medicine, University of California-Irvine, C362 Medical Sciences I, Irvine, CA, 92697, USA

    Wei Ling Lau, Shu-Man Liu, Sogol Pahlevan, Jun Yuan, Mahyar Khazaeli, Zhenmin Ni & Nosratola D. Vaziri

  2. Department of Pathology, University of California-Irvine, D440 Medical Sciences I, Irvine, CA, 92697, USA

    Jefferson Y. Chan

Authors
  1. Wei Ling Lau
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  2. Shu-Man Liu
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  3. Sogol Pahlevan
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Corresponding author

Correspondence to Wei Ling Lau.

Additional information

Wei Ling Lau and Shu-Man Liu have contributed equally to this work.

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Lau, W.L., Liu, SM., Pahlevan, S. et al. Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption. Dig Dis Sci 60, 1215–1222 (2015). https://doi.org/10.1007/s10620-014-3428-4

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  • DOI: https://doi.org/10.1007/s10620-014-3428-4

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