Epithelial-mesenchymal transition and its implications for fibrosis

Kalluri, Raghu; Neilson, Eric G.

doi:10.1172/jci200320530

Cited by 2,049 publications

(961 citation statements)

References 146 publications

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“…TGF-␤ is one of the cytokines released during the inflammatory response which activates fibroblasts to transform into myofibroblasts to produce ECM. Excessive production of TGF-␤1 was linked to tissue fibrosis during aging and pathological changes in many organs, including liver, lung, kidney, heart, skeletal muscle, and uterus (58)(59)(60). However, the molecular basis of this increased synthesis of TGF-␤ was unknown.…”

Section: Sirt3 Activates Gsk3␤mentioning

confidence: 99%

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Sundaresan

Bindu

Pillai

et al. 2016

Molecular and Cellular Biology

160

141

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Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is transforming growth factor ␤1 (TGF-␤1)-mediated transformation of fibroblasts into myofibroblasts, cells capable of synthesizing extracellular matrix. Here, we show that SIRT3 controls transformation of fibroblasts into myofibroblasts via suppressing the profibrotic TGF-␤1 signaling. We found that Sirt3 knockout (KO) mice with age develop tissue fibrosis of multiple organs, including heart, liver, kidney, and lungs but not whole-body SIRT3-overexpressing mice. SIRT3 deficiency caused induction of TGF-␤1 expression and hyperacetylation of glycogen synthase kinase 3␤ (GSK3␤) at residue K15, which negatively regulated GSK3␤ activity to phosphorylate the substrates Smad3 and ␤-catenin. Reduced phosphorylation led to stabilization and activation of these transcription factors regulating expression of the profibrotic genes. SIRT3 deacetylated and activated GSK3␤ and thereby blocked TGF-␤1 signaling and tissue fibrosis. These data reveal a new role of SIRT3 to negatively regulate aging-associated tissue fibrosis and discloses a novel phosphorylation-independent mechanism controlling the catalytic activity of GSK3␤.

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Section: Sirt3 Activates Gsk3␤mentioning

confidence: 99%

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Sundaresan

Bindu

Pillai

et al. 2016

Molecular and Cellular Biology

160

141

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“…EMT is also found to be associated with fibrosis in kidney, liver, lung and intestine. The lineage-tagging experiments demonstrated that during the course of kidney fibrosis in mice, about 30% are derived from the tubular epithelial cells of the kidney via EMT [23]. Indeed, EMT in chemotactic factors (CCL4)-induced liver fibrosis has taken place in hepatocytes, which has been revealed in transgenic mice [24], so do the alveolar epithelial cells during the pulmonary fibrosis induced by transforming growth factor β (TGF-β) [25].…”

Section: Overview Of the Epithelial-mesenchymal Transition (Emt)mentioning

confidence: 99%

The contribution of TGF-β in Epithelial–Mesenchymal Transition (EMT): Down-regulation of E-cadherin via snail

Yu¹,

Shen²,

Hong³

et al. 2015

neo

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TGF-β plays a central role in epithelial-mesenchymal transition (EMT), which is a highly conserved and reversible process that governs tumor development, invasion and metastasis. Through this transition, the epithelial cell acquires a migratory behavior which allows it to move away from the cell community and to integrate into the surrounding tissue. The cells lost epithelial phenotypes including the change of cell polarity and the loss of specialized cell-cell contacts, which related with the shortage of E-cadherin directly. The increasing reports indicated that TGF-β down-regulated the expression of E-cadherin through snail signaling pathway, which played an important role in the development of EMT. In this review, we summarized the contribution of TGF-β in EMT and discussed the molecular mechanism of snail signaling participating in the regulation of E-cadherin triggered by TGF-β.

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“…Myofibroblasts in the tubular interstitium are responsible for the fibrosis and are derived from several sources, including endogenous renal fibroblasts, stem cells, and epithelial-to-mesenchymal transition (EMT) of renal tubular cells [1, 2]. The latter is stimulated by mediators released from infiltrating inflammatory cells and can be induced in vitro by treating tubular epithelial cells with medium conditioned by activated peripheral blood mononuclear cells (aPBMC-CM) [3,4,5].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of Statins on Renal Epithelial-to-Mesenchymal Transition

et al. 2006

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Background/Aim: Recent studies have suggested that statins may play a role in the protection against renal failure which is independent of cholesterol reduction. Activation of RhoGTPases is a key step in renal tubular cells’ epithelial-to-mesenchymal transition (EMT) which contributes to renal interstitial fibrosis. We hypothesized that statins could act by inhibiting the synthesis of the isoprenoids, such as geranylgeranyl pyrophosphate, which is essential for membrane attachment and biological activity of RhoGTPases, RhoA and Rac1. Methods: Human proximal tubular epithelial cells (HK2) were used to examine the inhibitory effect of statins on EMT induced with medium conditioned by activated peripheral blood mononuclear cells. Results: Our study demonstrates that the statins lovastatin, simvastatin, and pravastatin inhibit HK2 cells to undergo EMT. Inhibition of EMT in HK2 cells with these statins resulted in a reduction of RhoA and Rac1 activation in both the cytoplasmic and membrane-bound forms, in preservation of the expression of the epithelial cell markers E-cadherin and cytokeratin-19, and in a decrease in Fn-EDA expression, a marker for the myofibroblast phenotype. The decreased levels of activated RhoA and Rac1 in both the cytoplasmic and membrane fractions of the cells were reversed by geranylgeranyl pyrophosphate and mevalonate, and thus attributable to the inhibition of isoprenylation of RhoGTPases by statins. Conclusion: This phenomenon could explain the beneficial effect of statins on EMT and on renal fibrosis prevention.

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Epithelial-mesenchymal transition and its implications for fibrosis

Cited by 2,049 publications

References 146 publications

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

The contribution of TGF-β in Epithelial–Mesenchymal Transition (EMT): Down-regulation of E-cadherin via snail

Inhibitory Effect of Statins on Renal Epithelial-to-Mesenchymal Transition

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