Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis

Strippoli, Raffaele; Moreno-Vicente, Roberto; Battistelli, Cecilia; Cicchini, Carla; Noce, Valeria; Amicone, Laura; Marchetti, Alessandra; Pozo, Miguel Á. del; Tripodi, Marco

doi:10.1155/2016/3543678

Cited by 104 publications

(122 citation statements)

References 112 publications

(157 reference statements)

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“…It has been reported that several signaling pathways or growth factors (TGFβ1/Smads, Wnt/β-catenin, and Notch) participate in EMT [27], among which TGF-β1 is the well-recognized induced factor of EMT and subsequent fibrosis [28]. Our previous studies also revealed that TGF-β1 was highly upregulated in EMT of peritoneum in vivo and HMrSV5 cells underwent EMT after treatment by TGF-β1 [29,30].…”

Section: Cell Physiolmentioning

confidence: 89%

The Role of TLR4 in M1 Macrophage-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells

Shi

Sheng

et al. 2016

Cell Physiol Biochem

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Background/Aims: Peritoneal fibrosis is a frequent complication of peritoneal dialysis that follows inflammation. It is recognized that epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs), plays a key role in fibrogenesis. However, the relationship between inflammatory macrophages and PMCs remains elusive. In this study, we investigated the effects of different polarized macrophages on EMT of HMrSV5 PMCs. Methods: Monocytes were polarized to M1/M2 macrophages before being added to HMrSV5 in direct or indirect contact. Morphological changes of HMrSV5 were observed and toll-like receptors 4 (TLR4) on macrophage surfaces was detected using flow cytometry. EMT markers and intracellular signals of HMrSV5 cells were assessed using real time-PCR and WB. Results: The typical epithelial cell morphology of HMrSV5 disappeared after co-culture with M1 macrophages and was accompanied by decreased E-cadherin and increased α-SMA, suggesting HMrSV5 undergo EMT. These effects depended on direct contact between the two cells, as indirect contact or co-culture with M2 macrophages had no effect. Intriguingly, we found TLR4 surface receptors were activated on sorted M1 cells in co-culture, and related signal adaptors, such as TRIF, were obviously upregulated. Conclusion: Direct contact with M1 macrophages induces EMT of PMCs, during which TRIF-dependent TLR4 signaling pathway was activated.

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Section: Cell Physiolmentioning

confidence: 89%

The Role of TLR4 in M1 Macrophage-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells

Shi

Sheng

et al. 2016

Cell Physiol Biochem

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“…miRNAs are indispensable for fibrosis, and a large number of miRNA families have been shown to modulate fibrosis [73]. Indeed, miRNAs are incorporated into exosomes, wherein they are more stable than in the cellular compartment.…”

Section: Exosomes Affect Fibrosis and Angiogenesis Via Exosomal Mirnasmentioning

confidence: 99%

Exosomes: The New Mediator of Peritoneal Membrane Function

Shi

Sheng³

2018

Kidney Blood Press Res

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Fibrosis and angiogenesis are the most common processes that result in progressive peritoneal tissue remodeling and, eventually, peritoneal membrane dysfunction. The role of exosomes, which contributes to intercellular communication, in these processes has been neglected. Various biomolecules, including DNA, mRNA, proteins, lipids, and particular certain miRNAs, can be transferred by exosomes to local, neighboring and distal cells. Upon stimulation by cytokines or other microenvironment stimuli, donor cells release a mass of exosomes to peritoneal mesothelial cells, further affecting fibrosis and angiogenesis. This important exosomes-mediated intracellular communication is thought to regulate peritoneal membrane function. Understanding the molecular mechanisms of these processes, targeting changes in exosomes and regulating exosomal miRNAs will advance therapeutic methods for protecting peritoneal membrane function.

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“…EMT is a reversible process by which epithelial cells are able to transform into cells with mesenchymal characteristics. Peritoneal mesothelial cells (PMCs) coexpress epithelial and mesenchymal markers under basal conditions, due to their mesodermal origin, which explains their enhanced plasticity [3]. PMCs that have undergone EMT exhibit an augmented ability to detach from basement membranes and invade into the submesothelial zone, leading to extracellular matrix (ECM) deposition and collagen formation.…”

Section: Introductionmentioning

confidence: 99%

Astragalus Inhibits Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells by Down-Regulating β-Catenin

Yu¹,

Shi²,

Sheng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) is a crucial event in the induction of peritoneal fibrosis (PF), in which canonical Wnt/β-catenin signaling participates. Smads signaling is reported to interact with β-catenin and synergistically regulates EMT. This study was aimed to reveal the effect of Astragalus on β-catenin in EMT of PMCs. Methods: To obtain the role of β-catenin in EMT, gene transfer into HMrSV5 cell line and rats has been achieved. After Astragalus treatment, EMT markers and signaling pathway-related indicators were detected by western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation and real time-PCR. Results: β-catenin knockdown suppressed EMT of HMrSV5 cells. Astragalus alleviated EMT of PMCs characterized by increased E-cadherin and decreased α-SMA and Vimentin. In rat model of peritoneal dialysis (PD), Astragalus attenuated peritoneal thickening and fibrosis. Astragalus down-regulated β-catenin by stabilizing the Glycogen synthase kinase-3β (GSK-3β)/β-catenin complex and further inhibited the nuclear translocation of β-catenin. Meanwhile, Astragalus down-regulated β-catenin by enhancing Smad7 expression. Silencing Smad7 antagonized the EMT-inhibitory effect of Astragalus. Conclusion: Astragalus inhibits EMT of PMCs by down-regulating β-catenin. The modulation of β-catenin in peritoneum can be a novel tool to prevent PF.

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Molecular Mechanisms Underlying Peritoneal EMT and Fibrosis

Cited by 104 publications

References 112 publications

The Role of TLR4 in M1 Macrophage-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells

The Role of TLR4 in M1 Macrophage-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells

Exosomes: The New Mediator of Peritoneal Membrane Function

Astragalus Inhibits Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells by Down-Regulating β-Catenin

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