Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis

Abstract

Kidney fibrosis is marked by an epithelial–to–mesenchymal transition (EMT) by tubular epithelial cells (TECs). Here we find that during renal fibrosis TECs acquire a partial EMT program during which they remain associated with their basement membrane and express markers of both epithelial and mesenchymal cells. The functional consequence of EMT program during fibrotic injury is an arrest in the G2 phase of the cell cycle and lower expression of several transporters in TECs. We also found that transgenic expression of Twist or Snai1 expression is sufficient to promote prolonged TGF-β1–induced G2 arrest of TECs, limiting their potential for repair and regeneration. Also, in mouse models of experimentally-induced renal fibrosis, conditional deletion of Twist1 or Snai1 in proximal TECs resulted in inhibition of the EMT program and the maintenance of TEC integrity, while restoring proliferation, de–differentiation–associated repair and regeneration of the kidney parenchyma and attenuating interstitial fibrosis. Thus, inhibition of EMT program in TECs during chronic renal injury represents a potential anti–fibrosis therapy

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…Similarly, it has been shown that resident renal epithelial cells undergo partial EMT that contributes to the interstitial fibrosis phenotype in kidney fibrosis [127,128]. This phenomenon has also been described in cardiac fibrosis [129].…”

The role of the complement system in cancer

“…Epithelial-mesenchymal transition (EMT) occurs in physiologic processes such as embryogenesis and organ development, and in pathologic conditions including tissue fibrosis and metastasis (78,79). Complement participates in EMT in murine models of renal injury and fibrosis (62,80,81).…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…Based on the current literature, therefore, it appears likely that de novo EndMT makes a modest contribution to the myofibroblast population in the adult heart. However, studies performed in other organs, such as the kidney, suggest that de novo EMT gives rise to fibroblast-like cells that adopt a partially transitioned state intermediate between epithelial cells and fibroblasts (Grande et al, 2015;Lovisa et al, 2015). This possibility is unexplored in the adult heart but may reconcile the apparent differences between lineagetracing studies on the origin of the cardiac fibroblast.…”