Resveratrol Mitigates Uremic Toxin-Induced Intestinal Barrier Dysfunction in Chronic Kidney Disease by Promoting Mitophagy and Inhibiting Apoptosis Pathways.

UNLABELLED

Chronic Kidney Disease (CKD) is a systemic progressive disorder related to uremic toxins. Uremic toxins disturb intestinal epithelial destruction and barrier dysfunction leading to gut-renal axis disorders in CKD. We examine the protective role of Resveratrol (RSV) against uremic toxin indoxyl sulphate (IS) related intestinal barrier disturbances among CKD.

METHODS

5/6 nephrectomized mice and isolated primary mouse intestinal epithelial cells (IEC-6) are used to assess the influence of IS on intestinal epithelial tight junction barriers. Serum biochemistry parameters, hematoxylin & eosin (H&E) and immunohistochemistry staining (IHC), Western blot analysis, q-PCR, and si-RNA targeted against AhR were used in this study.

RESULTS

IS decreases the expression of tight junction proteins (TJPs) ZO-1 and claudins, increases the apoptosis and impairs mitophagy within IECs. Treatment with RSV not only reduces the loss of TJPs but also modulates mitophagy markers LC3 and P62, and concurrently decreases the levels of apoptosis-related proteins. Significantly, RSV ameliorates intestinal barrier dysfunction in CKD by modulating mitophagy via the IRF1-DRP1 axis, restoring autophagy, and inhibiting apoptosis through the activation of the PI3K/Akt-Ho-1 anti-oxidant pathway, and mTOR regulated pathways.

CONCLUSION

This study establishes RSV as a potential therapeutic agent that can ameliorate gut-renal axis disturbances in CKD. These findings provide valuable insights into mechanisms underlying RSV RSV-mediated gut-renal axis, highlighting its effectiveness as a potential treatment option for CKD-associated intestinal barrier dysfunction.