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

MiR-126-3p Is Dynamically Regulated in Endothelial-to-Mesenchymal Transition during Fibrosis

“…Recent data suggests both cell free-miR-126 and EV-miR-126 as a negative regulation biomarker for acute myocardial infarction and cardiovascular disease. In addition, a study from Lovisa et al showed that EndMT was responsible for vascular leakage in kidney fibrosis and as previously discussed, neonatal miR126 −/− mice are susceptible to vascular leakage and develop with multiple vascular integrity defects [18,31]. Therefore, miR-126-3p could be involved in the EndMT-induced vascular leakage.…”

Ceria Nanoparticles Ameliorate Renal Fibrosis by Modulating the Balance Between Oxidative Phosphorylation and Aerobic Glycolysis

“…Metabolic reprogramming is the hallmark of kidney fibrosis with multiple dysregulated metabolic pathways, such as aerobic glycolytic, which has been detected in kidney fibrosis [24]. Furthermore, aerobic glycolytic is a critical factor that causes epithelial cell damage and inflammation [25].…”

Epithelial-to-Mesenchymal Transition in Fibrosis: Concepts and Targeting Strategies

“…The increase in glycolysis was proved to be detrimental as the treatment with the glycolysis inhibitor 3-bromopyruvate ameliorated tissue fibrosis (Lovisa et al, 2020;Yu et al, 2021). Moreover, genetic or pharmacological targeting of c-Myc by treatment with the JQ1 inhibitor reduced fibrosis, preserved the epithelial parenchyma, and restored the metabolic homeostasis (Lovisa et al, 2020). Whether inhibition of glycolysis is able to reduce EMT was not investigated; however, it is possible as EMT cells switch their metabolism from oxidative phosphorylation to glycolysis and scRNA-seq confirmed the downregulation of genes of the mitochondrial oxidative phosphorylation (Deshmukh et al, 2021).…”

“…Moreover, the activation of the mesenchymal program leads to the acquisition of a pro-inflammatory secretome profile which in turn fuels immune infiltration and further promotes fibrosis ( Grande et al, 2015 ; Lovisa et al, 2015 ). Similarly, the contribution of EndMT to the myofibroblast pool was determined as minor while having a significant impact on vascular integrity ( LeBleu et al, 2013 ; Lovisa et al, 2020 ).…”

“…Similarly, conditional deletion of Twist1 or Snail in endothelial cells (using Cdh5- and Tie1-Cre models) was recently shown to inhibit the cognate process of EndMT and protect from kidney fibrosis by limiting vascular leakage and the downstream hypoxia-driven metabolic rearrangements ( Balzer and Susztak, 2020 ; Lovisa et al, 2020 ). Tie2-driven conditional deletion of Twist1 in the endothelium was also shown to be associated with reduction of lung fibrosis ( Mammoto et al, 2013 ; Mammoto et al, 2016 ; Mammoto et al, 2018 ), while Tie2-driven deletion of Snail led to embryonic lethal vascular defects ( Wu et al, 2014 ).…”