Figure 10.

ET‐1 drives EMT and consequently fibrosis in the kidney. The cartoon depicts the epithelial‐to‐mesenchymal phenotypic shift induced by ET‐1 in the renal tubules. Tubular cells are tightly linked to adjacent cells by junctions (visualized as red dashes) under physiologic conditions. On binding of ET‐1, the ET_B receptor subtype triggers a cell phenotype switch by which cells start expressing mesenchymal markers such as αSMA and vimentin and gradually lose their epithelial markers, such as E‐cadherin, which is the major component of adherent junctions. The phenotypic switch is represented in this cartoon as a change of color from bluish‐violet to greenish. Hence, coexistence of blue and greenish denotes an intermediate phenotype, whereas greenish indicates a complete transition to the mesenchymal phenotype. The cells undergoing this switch also exhibit a loss of cell junctions alongside activation of MMP‐9, which promotes degradation of the basal membrane. These concomitant processes allow the modified cells to move toward the interstitium, where they start producing extracellular matrix proteins, including collagen (red and blue lines) that, by accumulating in the interstitium between tubules, leads to tubulointerstitial fibrosis. The magnified tubular cell illustrates in greater detail the intracellular pathways activated by ET‐1. Phosphorylation of MYPT, a member of the Rho/Rock pathway that leads to cytoskeleton contraction and cell motility, is activated, whereas YAP phosphorylation is prevented, thereby allowing entry of YAP into the nucleus and finally leading to transcription of target genes that promote cell migration. Dashed lines indicate yet not proven effects.