Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Int J Med Sci. 2024 Sep 16;21(13):2437-2449. doi: 10.7150/ijms.100963. eCollection 2024.
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.
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.
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.
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.
慢性肾脏病（CKD）是一种与尿毒症毒素有关的系统性进行性疾病。尿毒症毒素扰乱肠上皮细胞的破坏和屏障功能，导致 CKD 中的肠-肾轴紊乱。我们研究白藜芦醇（RSV）对 CKD 中尿毒症毒素吲哚硫酸（IS）相关肠屏障紊乱的保护作用。
5/6 肾切除术小鼠和分离的原代小鼠肠上皮细胞（IEC-6）用于评估 IS 对肠上皮紧密连接屏障的影响。本研究采用血清生化参数、苏木精和伊红（H&E）和免疫组织化学染色（IHC）、Western blot 分析、q-PCR 和针对 AhR 的 si-RNA。
IS 降低了紧密连接蛋白（TJPs）ZO-1 和 Claudin 的表达，增加了 IEC 中的细胞凋亡和损伤线粒体自噬。RSV 治疗不仅减少 TJPs 的丢失，而且还调节线粒体自噬标志物 LC3 和 P62，并同时降低凋亡相关蛋白的水平。重要的是，RSV 通过 IRF1-DRP1 轴调节线粒体自噬，恢复自噬，通过激活 PI3K/Akt-Ho-1 抗氧化途径和 mTOR 调节途径抑制凋亡，从而改善 CKD 中的肠-肾轴功能障碍。
本研究确立 RSV 是一种潜在的治疗药物，可改善 CKD 中的肠-肾轴紊乱。这些发现为 RSV 介导的肠-肾轴提供了有价值的见解，强调了其作为 CKD 相关肠屏障功能障碍的潜在治疗选择的有效性。
