Research ArticleFibrosis

Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis

See allHide authors and affiliations

Science Signaling  09 Jun 2020:
Vol. 13, Issue 635, eaaz2597
DOI: 10.1126/scisignal.aaz2597

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Leaky blood vessels to kidney fibrosis

Endothelial cells can undergo a cellular transdifferentiation program known as endothelial-to-mesenchymal transition (EndMT) in response to injury. Lovisa et al. discovered that EndMT in the kidney triggered tissue and metabolic changes that culminated in fibrosis (see also the Focus by Balzer and Susztak). Kidney injury activated Twist and Snail, transcription factors that mediate EndMT, resulting in vascular disruptions. The ensuing tissue hypoxia triggered a Myc-induced metabolic switch to glycolysis in tubular epithelial cells that culminated in fibrosis and compromised kidney function. Twist or Snail deficiency in endothelial cells, Myc deficiency in epithelial cells, or pharmacologically inhibiting glycolysis or Myc prevented kidney fibrosis and dysfunction after injury. These results identify the cellular cross-talk and the key proteins involved that could be targeted to prevent kidney fibrosis.

Abstract

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.

View Full Text

Stay Connected to Science Signaling