纤维化
肾
细胞生物学
癌症研究
转分化
间充质干细胞
生物
病理
上皮-间质转换
下调和上调
医学
内分泌学
干细胞
生物化学
基因
作者
Sara Lovisa,Eliot Fletcher-Sananikone,Hikaru Sugimoto,Janine Hensel,Sharmistha Lahiri,Alexandre Hertig,Gangadhar Taduri,Erica J. Lawson,Rajan Dewar,Ignacio Revuelta,Noritoshi Kato,Chang-Jiun Wu,Roland L. Bassett,Nagireddy Putluri,Michael Zeisberg,Elisabeth M. Zeisberg,Valerie S. LeBleu,Raghu Kalluri
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2020-06-09
被引量:54
标识
DOI:10.1126/scisignal.aaz2597
摘要
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.
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