Epithelial–mesenchymal plasticity in kidney fibrosis

Abstract

SummaryEpithelial–mesenchymal transition (EMT) is an important biological process contributing to kidney fibrosis and chronic kidney disease. This process is characterized by decreased epithelial phenotypes/markers and increased mesenchymal phenotypes/markers. Tubular epithelial cells (TECs) are commonly susceptible to EMT by various stimuli, for example, transforming growth factor‐β (TGF‐β), cellular communication network factor 2, angiotensin‐II, fibroblast growth factor‐2, oncostatin M, matrix metalloproteinase‐2, tissue plasminogen activator (t‐PA), plasmin, interleukin‐1β, and reactive oxygen species. Similarly, glomerular podocytes can undergo EMT via these stimuli and by high glucose condition in diabetic kidney disease. EMT of TECs and podocytes leads to tubulointerstitial fibrosis and glomerulosclerosis, respectively. Signaling pathways involved in EMT‐mediated kidney fibrosis are diverse and complex. TGF‐β1/Smad and Wnt/β‐catenin pathways are the major venues triggering EMT in TECs and podocytes. These two pathways thus serve as the major therapeutic targets against EMT‐mediated kidney fibrosis. To date, a number of EMT inhibitors have been identified and characterized. As expected, the majority of these EMT inhibitors affect TGF‐β1/Smad and Wnt/β‐catenin pathways. In addition to kidney fibrosis, these EMT‐targeted antifibrotic inhibitors are expected to be effective for treatment against fibrosis in other organs/tissues.

Up-regulation of long non-coding RNA H19 ameliorates renal tubulointerstitial fibrosis by reducing lipid deposition and inflammatory response through regulation of the microRNA-130a-3p/long-chain acyl-CoA synthetase 1 axis

“…The profibrotic response in renal tubular epithelial cells induced by TGF-β1 has been extensively utilized as an in vitro model to study renal tubulointerstitial fibrosis [ [34] , [35] , [36] , [37] ]. The EMT triggered by TGF-β1 closely mimics a crucial pathological event in the progression of renal tubulointerstitial fibrosis [ 38 ]. In this work, we constructed the in vitro model of renal tubulointerstitial fibrosis by stimulating human renal proximal tubular epithelial cells HK-2 with TGF-β1.…”

Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators

“…These changes consist of a loss of cell adhesion and polarity, while gaining the ability to migrate and invade, as well as the capacity to deposit excessive ECMs. These events have been described in various organs, including the cardiovascular system [ 53 ], kidneys [ 54 ], and lungs [ 55 ], and the intestine [ 56 ]. Additionally, it is noteworthy that besides EMT, mesenchymal-to-epithelial transition (MET) is possible and contributes to wound repair and oncogenesis [ 57 ].…”

Role of the epithelial barrier in intestinal fibrosis associated with inflammatory bowel disease: relevance of the epithelial-to mesenchymal transition

“…In the literature, there are three types of EMT described: the ones associated with embryogenesis/development (type-1 EMT); the ones involved in wound healing (type-2 EMT); and the ones associated with cancer progression (type-3 EMT) ( Marconi et al, 2021 ). Several studies have reported that damaged epithelial cells may act as crucial sources of fibroblasts and contribute to organ fibrosis through type-2 EMT in different fibrotic tissues ( Tennakoon et al, 2015 ; Rout-Pitt et al, 2018 ; Ortiz-Masiá et al, 2020a ; Macias-Ceja et al, 2022 ; Hadpech and Thongboonkerd, 2023 ) where specialized epithelial cells give rise to myofibroblasts with profibrotic and pro-inflammatory activity, which expresses α smooth muscle actin (α-SMA) and VIMENTIN but does not express epithelial markers, such as E-CADHERIN (CDH1), ZONULAE OCCLUDENTES (ZOS) or claudins. Various transcriptional factors regulate the process, such as SNAIL Family Transcriptional Repressor (SNAIL1/2), ZINC-FINGER E-BOX-BINDING (ZEB1/2), SLUG or TWIST transcription factors (TWIST1/2) ( Xu et al, 2019 ).…”