School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 211198, China.
Molecules. 2022 Apr 6;27(7):2344. doi: 10.3390/molecules27072344.
The latest progress in the field of renal fibrosis mainly focuses on the new concept of "partial epithelial-mesenchymal transition (pEMT)" to explain the contribution of renal tubular epithelial (RTE) cells to renal fibrosis and the crucial role of fatty acid oxidation (FAO) dysfunction in RTE cells for the development of renal fibrosis. FAO depression is considered to be secondary or occur simultaneously with pEMT. We explored the relationship between pEMT and FAO and the effect of rhein on them. Intragastric administration of rhein significantly improved the levels of BUN, Scr, α-SMA, collagen 1A and histopathological changes in UUO-rats. Transcriptomic and metabolomic analyses revealed that abnormal signaling pathways were involved in EMT and FAO disorders. RTE cell experiments showed that TGF-β could inhibit the activity of Cpt1a, resulting in ATP depletion and lipid deposition. Cpt1a inhibitor induced EMT, while Cpt1 substrate or rhein inhibited EMT, indicating that Cpt1a-mediated FAO dysfunction is essential for RTE cells EMT. Further studies showed that Cpt1a activity were regulated by SirT1/STAT3/Twist1 pathway. Rhein inhibits RTE cell EMT by promoting Cpt1a-mediated FAO through the SirT1/STAT3/Twist1 pathway. Surprisingly and importantly, our experiments showed that FAO depression occurs before EMT, and EMT is one of the results of FAO depression.
肾纤维化领域的最新进展主要集中在“部分上皮-间充质转化（pEMT）”的新概念上，以解释肾小管上皮（RTE）细胞对肾纤维化的贡献，以及 RTE 细胞中脂肪酸氧化（FAO）功能障碍在肾纤维化发展中的关键作用。FAO 抑制被认为是继发于或与 pEMT 同时发生的。我们探讨了 pEMT 与 FAO 的关系以及大黄酸对它们的影响。大黄酸灌胃给药可显著改善 UUO 大鼠的 BUN、Scr、α-SMA、胶原 1A 和组织病理学变化。转录组和代谢组学分析显示，异常信号通路参与 EMT 和 FAO 紊乱。RTE 细胞实验表明，TGF-β可抑制 Cpt1a 活性，导致 ATP 耗竭和脂质沉积。Cpt1a 抑制剂诱导 EMT，而 Cpt1 底物或大黄酸抑制 EMT，表明 Cpt1a 介导的 FAO 功能障碍是 RTE 细胞 EMT 的关键。进一步的研究表明，Cpt1a 活性受 SirT1/STAT3/Twist1 通路调节。大黄酸通过 SirT1/STAT3/Twist1 通路促进 Cpt1a 介导的 FAO 抑制 RTE 细胞 EMT。令人惊讶的是，也很重要的是，我们的实验表明，FAO 抑制发生在 EMT 之前，而 EMT 是 FAO 抑制的结果之一。
