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Rapamycin decreases the PM deterioration in a PD mouse model. Mice received a daily instillation of standard PD fluid (2 mL per day) through a intraperitoneal catheter during 4 weeks with or without the oral administration of Rapamycin (2 mg/kg/day: PDF, n = 5 , and PDF + Rapamycin, n = 6 ). A control group of mice that were only exposed to the presence of the catheter was also included (control; n = 6 ). Peritoneal samples were prepared and analyzed as described in Materials and Methods section. (a) Standard PD fluid exposure increases matrix deposition (blue stained zones) and the thickness of the PM (black lines), while Rapamycin administration significantly reduces these effects when measured in Masson’s trichrome staining (sections representative slides). Magnification 200x. (b) As shown in immunofluorescence staining of cytokeratin (red) and FSP-1 (green) (counterstained with DAPI in blue), PDF exposure-promoted MMT (cells coexpressing cytokeratin and FSP-1 with double positive staining, yellow) is reduced by Rapamycin administration. Magnification 400x. (c) The peritoneal thickness (μm) is increased in PDF group compared with control mice, and the group PDF with Rapamycin shows a significant reduction of thickness when compared with PDF group. Analysis of variance results in a significance of p = 0.001 (one-way ANOVA test). (d) Measurement of TGF-β1 (pg/mL) in the drained volumes shows a gentle increase (although not statistically significant) of this growth factor in PD fluid-instilled animals while Rapamycin administration tends to reduce TGF-β1 production. The analysis of variance results in a p value of 0.146 (one-way ANOVA test). (e) Numbers of mesothelial cells per field suffering MMT increase during PDF exposition, while Rapamycin is able to reduce the occurrence of this pathological process. The analysis of variance results in a significance of p < 0.0001 (one-way ANOVA test). Box plots graphics represent the median, minimum, and maximum values, as well as the 25th and 75th percentiles. Numbers above boxes depict means ± SE. Symbols represent the statistical differences between groups analyzed by Mann-Whitney U test.
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Preservation of peritoneal membrane (PM) is essential for long-term survival in peritoneal dialysis (PD). Continuous presence of PD fluids (PDF) in the peritoneal cavity generates chronic inflammation and promotes changes of the PM, such as fibrosis, angiogenesis, and lymphangiogenesis. Mesothelial-to-mesenchymal transition (MMT) and endothelial-to...
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Lymphatic absorption in the peritoneal cavity may contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphatic vessels develop during PD-related peritoneal fibrosis. Connective tissue growth factor (CTGF, also called CCN2) is an important determinant of fibrotic tissue remodeling, but little is known about its possible involvement i...
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... Endothelial-mesenchymal transition (EndoMT)EndoMT is one of the important pathogeneses of peritoneal fibrosis, from which approximately 3%-5% of submesothelial fibroblasts in peritoneal dialysis originate (González-Mateo et al., 2015). Only a few studies on peritoneal fibrosis focus on endothelial cell-(myo)fibroblast crosstalk, proposing. ...
... Rapamycin can inhibit angiogenesis by reducing the production of VEGF or blocking its receptor. In PD rat model, rapamycin can reduce submesothelial CD31 vessels and the number of CD31+FSP1+endothelial cells, indicating that rapamycin decreased PD-induced angiogenesis and Endo-MT (González-Mateo et al., 2015). However, there are few studies on the mechanism of endothelial mesenchymal transition in PD-related peritoneal fibrosis. ...
Long-term peritoneal dialysis (PD) causes structural and functional alterations of the peritoneal membrane. Peritoneal deterioration and fibrosis are multicellular and multimolecular processes. Under stimulation by deleterious factors such as non-biocompatibility of PD solution, various cells in the abdominal cavity show differing characteristics, such as the secretion of different cytokines, varying protein expression levels, and transdifferentiation into other cells. In this review, we discuss the role of various cells in the abdominal cavity and their interactions in the pathogenesis of PD. An in-depth understanding of intercellular communication and inter-organ communication in PD will lead to a better understanding of the pathogenesis of this disease, enabling the development of novel therapeutic targets.
... In this research, treatment with the mTOR inhibitor rapamycin (RAPA) and PI3K inhibitor LY294002 activated autophagy and alleviated PF in vivo and in vitro, thereby upregulating E-cadherin and zonula occludens-1 (ZO-1) and downregulating alpha-smooth muscle actin (α-SMA) and ferroptosis suppressor protein 1 (Jia et al., 2022). In addition, RAPA, which can induce autophagy by inhibiting MTORC1 expression, relieved peritoneal thickening, angiogenesis, lymphangiogenesis, MMT, and endothelial-to-mesenchymal transition (Endo-MT) and improved UF in a mouse PD model (González-Mateo et al., 2015). Finally, micheliolide (MCL), a natural guaianolide sesquiterpene lactone, which promoted autophagy in db/db mice at a low dose, inhibited TGF-β1-induced ECM accumulation by activating autophagy in PF mouse models and the HPMC cell line (HMrSV5) (Zhong et al., 2018;Li et al., 2019b). ...
Peritoneal dialysis (PD) is a widely accepted renal replacement therapy for patients with end-stage renal disease (ESRD). Morphological and functional changes occur in the peritoneal membranes (PMs) of patients undergoing long-term PD. Peritoneal fibrosis (PF) is a common PD-related complication that ultimately leads to PM injury and peritoneal ultrafiltration failure. Autophagy is a cellular process of "self-eating" wherein damaged organelles, protein aggregates, and pathogenic microbes are degraded to maintain intracellular environment homeostasis and cell survival. Growing evidence shows that autophagy is involved in fibrosis progression, including renal fibrosis and hepatic fibrosis, in various organs. Multiple risk factors, including high-glucose peritoneal dialysis solution (HGPDS), stimulate the activation of autophagy, which participates in PF progression, in human peritoneal mesothelial cells (HPMCs). Nevertheless, the underlying roles and mechanisms of autophagy in PF progression remain unclear. In this review, we discuss the key roles and potential mechanisms of autophagy in PF to offer novel perspectives on future therapy strategies for PF and their limitations.
... In mice, paricalcitol reduced PDF-induced peritoneal by modulating Th17 and Treg response [190]. Rapamycin, another known autophagy inducer, has been shown to exert protective effects of PDF exposure models, these effects include a reduced PM thickness, decreased peritoneal fibrosis, improved PM transport function [191], reduced angiogenesis and lymphangiogenesis [192], decreased MMT and endothelial-to-mesenchymal transition [192,193] and improved lipid metabolism [194]. ...
... In mice, paricalcitol reduced PDF-induced peritoneal by modulating Th17 and Treg response [190]. Rapamycin, another known autophagy inducer, has been shown to exert protective effects of PDF exposure models, these effects include a reduced PM thickness, decreased peritoneal fibrosis, improved PM transport function [191], reduced angiogenesis and lymphangiogenesis [192], decreased MMT and endothelial-to-mesenchymal transition [192,193] and improved lipid metabolism [194]. ...
Chronic kidney disease (CKD) incidence is growing worldwide, with a significant percentage of CKD patients reaching end-stage renal disease (ESRD) and requiring kidney replacement therapies (KRT). Peritoneal dialysis (PD) is a convenient KRT presenting benefices as home therapy. In PD patients, the peritoneum is chronically exposed to PD fluids containing supraphysiologic concentrations of glucose or other osmotic agents, leading to the activation of cellular and molecular processes of damage, including inflammation and fibrosis. Importantly, peritonitis episodes enhance peritoneum inflammation status and accelerate peritoneal injury. Here, we review the role of immune cells in the damage of the peritoneal membrane (PM) by repeated exposure to PD fluids during KRT as well as by bacterial or viral infections. We also discuss the anti-inflammatory properties of current clinical treatments of CKD patients in KRT and their potential effect on preserving PM integrity. Finally, given the current importance of coronavirus disease 2019 (COVID-19) disease, we also analyze here the implications of this disease in CKD and KRT.
... Given the capability of TGF-β to promote the activation of PI3K/mTOR pathway [117], it has been demonstrated that the inhibition of mTOR complex activity by rapamycin was able to prevent EndoMT in vitro and ex vivo [135,136] and to improve fibrosis in two different mouse models of SSc [137]. Clinically, treatment with rapamycin was shown to improve skin stiffness, with good tolerability, in a small number of SSc patients [138][139][140]. ...
In systemic sclerosis (SSc), abnormalities in microvessel morphology occur early and evolve into a distinctive vasculopathy that relentlessly advances in parallel with the development of tissue fibrosis orchestrated by myofibroblasts in nearly all affected organs. Our knowledge of the cellular and molecular mechanisms underlying such a unique relationship between SSc-related vasculopathy and fibrosis has profoundly changed over the last few years. Indeed, increasing evidence has suggested that endothelial-to-mesenchymal transition (EndoMT), a process in which profibrotic myofibroblasts originate from endothelial cells, may take center stage in SSc pathogenesis. While in arterioles and small arteries EndoMT may lead to the accumulation of myofibroblasts within the vessel wall and development of fibroproliferative vascular lesions, in capillary vessels it may instead result in vascular destruction and formation of myofibroblasts that migrate into the perivascular space with consequent tissue fibrosis and microvessel rarefaction, which are hallmarks of SSc. Besides endothelial cells, other vascular wall-resident cells, such as pericytes and vascular smooth muscle cells, may acquire a myofibroblast-like synthetic phenotype contributing to both SSc-related vascular dysfunction and fibrosis. A deeper understanding of the mechanisms underlying the differentiation of myofibroblasts inside the vessel wall provides the rationale for novel targeted therapeutic strategies for the treatment of SSc.
... It has been shown that this drug may prevent EndMT, by suppressing the ECs ability to migrate and to degrade the extracellular matrix [183]. In fact, it has been reported that, in mice undergoing peritoneal dialysis, the treatment with rapamycin reduces the peritoneal membrane thickness and EndMT process, suggesting that rapamycin has a protective effect on peritoneal membrane during peritoneal dialysis, through an anti-fibrotic and anti-proliferative effect [184]. On the contrary, it has been recently reported that, although, rapamycin is able to suppress senescence-associated phenotype in human coronary artery ECs, the treatment with rapamycin, in this model, may promote EndMT, through the activation of autophagy [185]. ...
Systemic Sclerosis (SSc) is an autoimmune disease characterized by significant vascular alterations and multi organs fibrosis. Microvascular alterations are the first event of SSc and injured endothelial cells (ECs) may trans‐differentiate toward myofibroblasts, the cells responsible of fibrosis and collagen deposition. This process is identified as endothelial‐to‐mesenchymal transition (EndMT) and the understanding its development is pivotal to identify early pathogenetic events and new therapeutic target for SSc.
In this review, we have highlighted the molecular mechanism of EndMT and summarized the evidence of the role played by EndMT during the development of progressive fibrosis in SSc, also exploring the possible therapeutic role of its inhibition.
... In cultured human peritoneal mesothelial cells, rapamycin showed a mild protective effect on MMT, increasing E-cadherin and decreasing α-SMA levels [258]. Additionally, rapamycin was protective in experimental PD, reducing PM thickness, peritoneal fibrosis, angiogenesis, lymphangiogenesis, MMT, and Endo-MT while improving peritoneal membrane transport and lipidic metabolism [259][260][261][262]. These studies suggest that mTOR inhibition by rapamycin may be an alternative to reducing IL-17A production in PD (Figure 4). ...
Chronic kidney disease (CKD) is a health problem reaching epidemic proportions. There is no cure for CKD, and patients may progress to end-stage renal disease (ESRD). Peritoneal dialysis (PD) is a current replacement therapy option for ESRD patients until renal transplantation can be achieved. One important problem in long-term PD patients is peritoneal membrane failure. The mechanisms involved in peritoneal damage include activation of the inflammatory and immune responses, associated with submesothelial immune infiltrates, angiogenesis, loss of the mesothelial layer due to cell death and mesothelial to mesenchymal transition, and collagen accumulation in the submesothelial compact zone. These processes lead to fibrosis and loss of peritoneal membrane function. Peritoneal inflammation and membrane failure are strongly associated with additional problems in PD patients, mainly with a very high risk of cardiovascular disease. Among the inflammatory mediators involved in peritoneal damage, cytokine IL-17A has recently been proposed as a potential therapeutic target for chronic inflammatory diseases, including CKD. Although IL-17A is the hallmark cytokine of Th17 immune cells, many other cells can also produce or secrete IL-17A. In the peritoneum of PD patients, IL-17A-secreting cells comprise Th17 cells, γδ T cells, mast cells, and neutrophils. Experimental studies demonstrated that IL-17A blockade ameliorated peritoneal damage caused by exposure to PD fluids. This article provides a comprehensive review of recent advances on the role of IL-17A in peritoneal membrane injury during PD and other PD-associated complications.
... Currently, several drugs have been tested as potential EndMT inhibitors. The mTOR inhibitor rapamycin is able to block EndMT, either by preventing EC migration and matrix degradation (Gao et al., 2011) or by lowering TGF-β, TNF-α and VEGF levels (Gonzalez-Mateo et al., 2015). Spironolactone, an aldosterone receptor-blocker, abrogates EndMT in a model of fibrosis, by blocking TGF-β and Notch signaling (Chen et al., 2015). ...
Cancer is one of the most important causes of morbidity and mortality worldwide. Tumor cells grow in a complex microenvironment constituted of immune, stromal, and vascular cells that supports growth, angiogenesis, and metastasis. Endothelial cells (ECs) are major components of the vascular microenvironment. These cells have been described for their plasticity and potential to transdifferentiate into mesenchymal cells through a process known as endothelial-to-mesenchymal transition (EndMT). This complex process is controlled by various factors, by which ECs convert into a phenotype characterized by mesenchymal protein expression and motile, contractile morphology. Initially described in normal heart development, EndMT is now identified in several pathologies, and especially in cancer. In this review, we highlight the process of EndMT in the context of cancer and we discuss it as an important adaptive process of the tumor microenvironment that favors tumor growth and dissemination but also resistance to treatment. Thus, we underline targeting of EndMT as a potential therapeutic strategy.
... A range of agents, such as tamoxifen; glucocorticoids; vascular endothelial growth factor (VEGF), Neuropilin1 (NRP-1), MMP or cyclooxygenase (COX) inhibitors; mTOR inhibition (rapamycin); LMW heparin; adrenergic β1-receptor blockers (nebivolol); angiotensin I receptor (AT1-R) antagonists; and vitamin D receptor (VDR) agonists (calcitriol) have been investigated in EPS, with varying efficacy. This suggests that the profound late changes associated with MMT may be difficult to completely reverse [46][47][48][49][50]. ...
... By reversing cytoplasmic glycolysis and lactate formation and decreasing stromal fibrosis, tamoxifen can enhance T cell immunosurveillance in the tumor microenvironment (TME) and potentially improve chemotherapy delivery to tumors. Tamoxifen inhibits cancer cell interactions with platelets, which decreases platelet activation and the release of TGF-β1, platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), interleukin 6 (IL-6) and insulin like growth factor (IGF-1) from platelets into the TME [1,46,47,54]. ...
... Therapeutic strategies to minimize MMT in EPS include direct TGF-β1 blockade, monoclonal anti-RAGE antibodies, SMAD7 transgene expression, BMP-7, BMP-4, rapamycin, anti-CTGF antibodies, microRNA30a, rosiglitazone, or Src inhibition [46,49,50,[123][124][125][126]. Oral rapamycin, which inhibits mTOR, has been shown to reduce peritoneal thickening, inflammation, angiogenesis, and lymphangiogenesis by the blockade of HIF-1α, TGF-β1 and VEGF in murine models of PD induced EPS [46]. ...
In chronic peritoneal diseases, mesothelial-mesenchymal transition is determined by cues
from the extracellular environment rather than just the cellular genome. The transformation of
peritoneal mesothelial cells and other host cells into myofibroblasts is mediated by cell membrane
receptors, Transforming Growth Factor β1 (TGF-β1), Src and Hypoxia-inducible factor (HIF). This
article provides a narrative review of the reprogramming of mesothelial mesenchymal transition in
chronic peritoneal diseases, drawing on the similarities in pathophysiology between encapsulating
peritoneal sclerosis and peritoneal metastasis, with a particular focus on TGF-β1 signaling and
estrogen receptor modulators. Estrogen receptors act at the cell membrane/cytosol as tyrosine
kinases that can phosphorylate Src, in a similar way to other receptor tyrosine kinases; or can
activate the estrogen response element via nuclear translocation. Tamoxifen can modulate estrogen
membrane receptors, and has been shown to be a potent inhibitor of mesothelial-mesenchymal
transition (MMT), peritoneal mesothelial cell migration, stromal fibrosis, and neoangiogenesis in
the treatment of encapsulating peritoneal sclerosis, with a known side effect and safety profile. The
ability of tamoxifen to inhibit the transduction pathways of TGF-β1 and HIF and achieve a
quiescent peritoneal stroma makes it a potential candidate for use in cancer treatments. This is
relevant to tumors that spread to the peritoneum, particularly those with mesenchymal
phenotypes, such as colorectal CMS4 and MSS/EMT gastric cancers, and pancreatic cancer with its
desmoplastic stroma. Morphological changes observed during mesothelial mesenchymal transition
can be treated with estrogen receptor modulation and TGF-β1 inhibition, which may enable the
regression of encapsulating peritoneal sclerosis and peritoneal metastasis.
... Recently, several drugs in clinical testing have been reported to inhibit EndMT in various animal disease models (Table 1). These drugs inhibit EndMT by targeting various signaling molecules, such as DPP-4 25,96 , Smad 97 , TGF-β 97-99 , AMPK 100 , and other proteins 28,[101][102][103][104][105][106] . ...
Endothelial-to-mesenchymal transition (EndMT) involves the phenotypic conversion of endothelial-to-mesenchymal cells, and was first discovered in association with embryonic heart development. EndMT can regulate various processes, such as tissue fibrosis and cancer. Recent findings have shown that EndMT is related to resistance to cancer therapy, such as chemotherapy, antiangiogenic therapy, and radiation therapy. Based on the known effects of EndMT on the cardiac toxicity of anticancer therapy and tissue damage of radiation therapy, we propose that EndMT can be targeted as a strategy for overcoming tumor resistance while reducing complications, such as tissue damage. In this review, we discuss EndMT and its roles in damaging cardiac and lung tissues, as well as EndMT-related effects on tumor vasculature and resistance in anticancer therapy. Modulating EndMT in radioresistant tumors and radiation-induced tissue fibrosis can especially increase the efficacy of radiation therapy. In addition, we review the role of hypoxia and reactive oxygen species as the main stimulating factors of tissue damage due to vascular damage and EndMT. We consider drugs that may be clinically useful for regulating EndMT in various diseases. Finally, we argue the importance of EndMT as a therapeutic target in anticancer therapy for reducing tissue damage.
... [15][16][17] Sirolimus known as a mTOR inhibitor has an antiproliferative effect on lymphatic vessels, and is clinically used for a difficult-to-treat lymphatic anomalies. 12,13,[18][19][20] Sirolimus binds the FK-binding protein 12, resulting in a complex that prevents phosphorylation and activation of 4EBP1 and S6K1. 21,22 The phosphorylation of 4EBP1 and S6K1 has a stimulatory function in the production of ribosomal components necessary for protein synthesis and cell cycle. ...
The mammalian target of rapamycin (mTOR) inhibitor sirolimus is an effective treatment for difficult‐to‐treat lymphatic anomalies. However, little is known about the expression of mTOR pathway components in lymphatic anomalies. Here we investigated the expression pattern of mTOR pathway components and their phosphorylated forms (mTOR, p‐mTOR, 4EBP1, p‐4EBP1, S6K1 and p‐S6K1) in normal lymphatic vessels and lymphatic anomalies using immunohistochemistry. We studied 18 patients of lymphatic anomalies, including lymphatic malformation (LM, n = 14), Kaposiform lymphangiomatosis (KLA, n = 2) and Kaposiform hemangioendothelioma (KHE, n = 2). Normal lymphatic vessels expressed 4EBP1, S6K1 and p‐S6K1, but not p‐4EBP1, mTOR or p‐mTOR. The mTOR was detected in all lymphatic anomalies, whereas its activation form p‐mTOR was detected in half cases of KLA and KHE but not in LM. All lymphatic anomalies expressed S6K1 and its activated form p‐S6K1. The expression of 4EBP1 was also found in all lymphatic anomalies, but its activation was detected in approximately half of them. The activation of mTOR was seen in tumor (KLA and KHE) but not in malformation (LM), whereas the activation of S6K1 and 4EBP1 was seen in all and half of lymphatic anomalies, respectively.
