#1921 Resveratrol improves the indoxyl sulfate-induced intestinal damage by promoting mitophagy and inhibiting apoptosis pathways

Abstract

Abstract Background and Aims Chronic Kidney Disease (CKD) represents a systemic condition marked by progressive impairment stemming from the pathological effects of uremic toxins. There are noted interactions between these toxins and the intestinal microbiota, leading to disruption of metabolic and immune pathways central to the gut-renal axis in patients with CKD. The present study examines the protective properties of Resveratrol (RSV), which functions as an antagonist to the aryl hydrocarbon receptor (AhR), against the adverse effects of the uremic toxin, indoxyl sulfate (IS), in relation to intestinal harm within the context of CKD. Method Our research utilized 5/6 nephrectomized mice and isolated primary mouse intestinal cells to assess the influence of IS on the development of tight junction barriers within the intestinal epithelium and overall cellular health within the intestine. Serum biochemistry assessments, hematoxylin & eosin (H&E) and immunohistochemistry staining (IHC), Western blot tests, q-PCR, and si-RNA targeted against AhR were used in the study. Results Experiments carried out on 5/6 nephrectomized mice and IEC-6 cell lines disclosed that IS compromises the integrity of the intestinal barrier, affecting the tight junction proteins (TJPs), along with perturbing mitophagy through the upregulation of IRF1 and inhibition of DRP1. RSV mitigates intestinal barrier dysfunction by promoting the expression of TJPs including zona occludens 1 (ZO-1), occludin, claudin-1, and claudin-2 proteins in uremic conditions. It also reverses the IS-related negative impacts on mitophagy. Additionally, RSV exerts antioxidant defenses by enhancing the PI3K/Akt/Nrf2 signaling pathway and decreasing cellular apoptosis via modulation of Bcl-2/Bax/cleaved caspase 3/cytochrome C/PARP-1 pathways. Conclusion Our findings highlight the promise of RSV as an agent capable of mitigating intestinal barrier dysfunction in CKD. This contributes substantial findings with implications for the modulation of the gut-renal axis.