Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of Twist1 (which encodes Twist) or Snai1 (which encodes Snail) in VE-cadherin⁺ or Tie1⁺ endothelial cells inhibited the emergence of EndMT and improved kidney fibrosis in two different kidney injury/fibrosis mouse models. Suppression of EndMT limited peritubular vascular leakage, reduced tissue hypoxia, and preserved tubular epithelial health and function. Hypoxia, which was exacerbated by EndMT, resulted in increased Myc abundance in tubular epithelial cells, enhanced glycolysis, and suppression of fatty acid oxidation. Pharmacological suppression or epithelial-specific genetic ablation of Myc in tubular epithelial cells ameliorated fibrosis and restored renal parenchymal function and metabolic homeostasis. Together, these findings demonstrate a functional role for EndMT in the response to kidney capillary endothelial injury and highlight the contribution of endothelial-epithelial cross-talk in the development of kidney fibrosis with a potential for therapeutic intervention.

内皮-间充质转化 (EndMT) 是一种细胞转分化程序，其中内皮细胞部分失去其内皮特性并获得间充质样特征。肾毛细血管内皮细胞可以经历 EndMT 与肾实质的持续损伤。EndMT 在肾纤维化中的功能后果仍未得到探索。在这里，我们研究了内皮细胞中 Twist 或 Snail 缺乏对肾纤维化中 EndMT 的影响。在 VE-cadherin ⁺或 Tie1 ^{+ 中}条件性删除Twist1（编码 Twist）或Snai1（编码 Snail）在两种不同的肾损伤/纤维化小鼠模型中，内皮细胞抑制 EndMT 的出现并改善肾纤维化。EndMT 的抑制限制了管周血管渗漏，减少了组织缺氧，并保持了管状上皮的健康和功能。EndMT 加剧的缺氧导致肾小管上皮细胞中 Myc 丰度增加、糖酵解增强和脂肪酸氧化抑制。肾小管上皮细胞中 Myc 的药理学抑制或上皮特异性基因消融可改善纤维化并恢复肾实质功能和代谢稳态。一起，