EMT–MET in renal disease: Should we curb our enthusiasm?

Galichon, Pierre; Finianos, Serge; Hertig, Alexandre

doi:10.1016/j.canlet.2013.04.018

Cited by 40 publications

(32 citation statements)

References 46 publications

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“…Renal tubular epithelial-mesenchymal transition (EMT) is regarded as an important cause leading to renal interstitial fibrosis [1,2], but this issue remains controversial [3,4]. The EMT process is characterized by the loss of epithelial markers, such as E-cadherin, zonula occludens-1 (ZO-1) and cytokeratin, and the acquisition of new mesenchymal markers, including vimentin, α-smooth muscle actin (α-SMA), fibroblast-specific protein-1 (Fsp-1) and fibronectin [5,6].…”

Section: Introductionmentioning

confidence: 99%

Egr-1 Mediates Chronic Hypoxia-Induced Renal Interstitial Fibrosis via the PKC/ERK Pathway

et al. 2014

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Background: Chronic hypoxia-induced epithelial-to-mesenchymal transition (EMT) is a crucial process in renal fibrogenesis. Egr-1, as a transcription factor, has been proven to be important in promoting EMT. However, whether it functions in hypoxia-induced renal tubular EMT has not been fully elucidated. Methods: Egr-1 were detected at mRNA and protein levels by qPCR and Western blot analysis respectively after renal epithelial cells were subjected to hypoxia treatment. Meanwhile, EMT phenotype was also observed through identification of relevant EMT-specific markers. siRNA was used to knock down Egr-1 expression and subsequent changes were observed. Specific PKC and MAPK/ERK inhibitors were employed to determine the molecular signaling pathway involved in Egr-1-mediated EMT phenotype. In vivo assays using rat remnant kidney model were used to validate the in vitro results. Furthermore, Egr-1 expression was examined in the samples of CKD patients with the clinical relevance revealed. Results: Hypoxia treatment enhanced the mRNA and protein levels of Egr-1 in HK-2 cells, which was accompanied by a reduced expression of the epithelial marker E-cadherin and an enhanced expression of the mesenchymal marker Fsp-1. Downregulation of Egr-1 with siRNA reversed hypoxia-induced EMT. Using the specific inhibitors to protein kinase C (calphostin C) or MAPK/ERK (PD98059), we identified that hypoxia induced Egr-1 expression through the PKC/ERK pathway. In addition, the upregulation of Egr-1 raised endogenous Snail levels, and the downregulation of Snail inhibited Egr-1-mediated EMT in HK-2 cells. Through in vivo assays using rat remnant kidney and CKD patients' kidney tissues, we found that Egr-1 and Snail were overexpressed in tubular epithelial cells with EMT. Conclusion: Egr-1 may be an important regulator of the development of renal tubular EMT induced by hypoxia through the PKC/ERK pathway and the activation of Snail. Targeting Egr-1 expression or activity might be a novel therapeutic strategy to control renal fibrosis.

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Section: Introductionmentioning

confidence: 99%

Egr-1 Mediates Chronic Hypoxia-Induced Renal Interstitial Fibrosis via the PKC/ERK Pathway

et al. 2014

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“…These include the clear incorporation of the majority of such cells within the proximal-tubule walls under both normal (unoperated/sham-operated) and pathological situations (UUO), the morphology of which suggests a spectrum of differentiation from a primitive form to a mature tubular cell. In addition, their staining against mesenchymal proteins (e.g., vimentin) could be construed as indicative of their existence in a relatively stable state of “epithelial phenotypic change” such as postulated for epithelial cells by Galichon et al (2013). While not found throughout the entire proximal tubule, the distribution of diformazan-positive cells is more or less random (“stochastic”) within the S3 segment, that portion of the proximal tubule shown to be the most susceptible to damaging conditions.…”

Section: Discussionmentioning

confidence: 99%

A population of mitochondrion-rich cells in the pars recta of mouse kidney

et al. 2015

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Following perfusion of adult mouse kidney with a solution of nitroblue tetrazolium (NBT), certain epithelial cells in the pars recta (S3) segments of proximal tubules react to form cytoplasmic deposits of blue diformazan particles. Such cells are characterized by dark cytoplasm, small and often elliptical nuclei, elaborate, process-bearing profiles, and abundant mitochondria. The atypical epithelial cells display the additional characteristic of immunoreactivity for a wide spectrum of antigens, including mesenchymal proteins such as vimentin. Though present in kidneys of untreated or sham-operated animals, they are particularly evident under experimental conditions such as unilateral ureteral obstruction (UUO), appearing in both contralateral and obstructed kidneys over the course of a week's duration, but disappearing from the obstructed kidney as it undergoes the profound atrophy attributable to deterioration of the population of its proximal tubules. The cells do not appear in neonatal kidneys, even those undergoing UUO, but begin to be recognizable soon after weaning (28 days). It is possible that diformazan-positive cells in the mouse S3 tubular segment constitute a resident population of cells that can replenish or augment the tubule. Although somewhat similar cells, with dark cytoplasm and vimentin expression, have been described in human, rat, and transgenic mouse kidney (Smeets et al., 2013; Berger et al., 2014), those cells—known as “scattered tubule cells” or “proximal tubule rare cells” differ from the S3-specific cells in that they are present throughout the entire proximal tubule, often lack a brush border, and have only few mitochondria.

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“…Actuellement, la description des phé nomè nes de TEM, incluant l'acquisition de capacité de migration et d'invasion des cellules é pithé liales, reste controversé e [11]. Il est cependant admis que la souffrance des cellules tubulaires serait à l'origine d'une reprogrammation cellulaire au cours de laquelle les cellules é pithé liales subiraient des modifications phé notypiques et exprimeraient des marqueurs mé senchymateux [12].…”

Section: Fibrogenè Se Ré Naleunclassified