Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

Abstract

Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also occurs in injured hepatocytes and hepatic progenitor cells (HPCs), as well as ductular reaction-related bile epithelia. Interestingly, the ductular reaction contributes partly to hepatocarcinogenesis of HPCs, and further, regenerating cholangiocytes after injury may be derived from hepatic stellate cells via mesenchymal to epithelia transition, a reverse phenomenon of type 2 EMT. Possible pathogenesis of type 2 EMT and its differences between renal and hepatic fibrosis are reviewed based on our experimental data.

Sequential Wnt Agonist Then Antagonist Treatment Accelerates Tissue Repair and Minimizes Fibrosis

“…Wnt produced by both tubular cells and fibroblasts participates in both repair of injured tissue and stimulation of fibrosis [21][22][23][24] . In particular, Wnt signaling stimulates cell state transitions, including epithelial-to-mesenchymal transition (EMT) and partial EMT (pEMT), which contribute to both tissue repair and many chronic fibrotic diseases 4,25,26 . After AKI, some kidney tubular epithelial cells undergo pEMT and some activated fibroblasts become myofibroblasts, the latter of which is a critical event in the development of fibrosis 27,28 .…”

Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways

“…The stimulation of the MAPK pathway may refect an initial increase in reactive oxygen species (ROS) signaling upstream from MAPK and the reduction in oxidative stress by Ang-(1-7) may potentially attenuate MAPK stimulation of [37,38]. Consistent with this proposed pathway, Ang-(1-7) blocked Ang II-induced migration and TGF-β and collagen expression of pulmonary myofibroblasts associated with a reduction in ROS and NOX 4 expression [17].…”

“…Moreover, comparable effects to Ang-(1-7) on pulmonary myofibroblasts were achieved with the ROS scavenger tempol and the NAD(P)H oxidase inhibitors apocynin and DPI [17]. Although the intracellular sources of ROS in fibrosis are not well-defined, the role of mitochondrial ROS may constitute an additional pathway to the stimulation of TGF-β, EMT and fibrosis [37,39,40]. Indeed, we recently identified a MEP-Ang-(1-7)-AT7/MasR pathway in mitochondria isolated from the sheep kidney that may contribute to cellular redox balance and could potentially influence myofibroblast transition [41].…”

“…An intriguing albeit controversial aspect of fibrosis is the role of myofibroblasts derived from resident epithelial, endothelial and pericyte cells, as well as fibroblasts [37,43]. Myofibroblast transition results in a more secretory and migratory phenotype that may ultimately promote tissue fibrosis, as well as depleting the local population of normal cells.…”

“…Myofibroblast transition results in a more secretory and migratory phenotype that may ultimately promote tissue fibrosis, as well as depleting the local population of normal cells. TGF-β is a prominent stimulus for myofibroblast formation, and likely contributes to myofibroblast transition elicited by other agents including Ang II, advanced glycation products (AGEs), aldosterone, and endothelin, as well as hypoxic and hyperglycemia conditions [37,38,44,45]. Treatment with Ang-(1-7) reversed the epithelial to mesenchymal or myofibroblast transition (EMT) of NRK-52 cells exposed to high glucose that was associated with reduced TGF-β expression and attenuated MAPK activation [46].…”