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Takao Masaki - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the h3k4 methyltransferase set7 9 ameliorates Peritoneal Fibrosis
PLOS ONE, 2018Co-Authors: Ryo Tamura, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Toshinori Ueno, Kazuya Maeda, Takao MasakiAbstract:Transforming growth factor-β1 (TGF-β1) is a major mediator of Peritoneal Fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of Fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on Peritoneal Fibrosis in mice and in human Peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of Peritoneal dialysis (PD) patients. Murine Peritoneal Fibrosis was induced by intraPeritoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-β1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis.
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Inhibition of the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis
PloS one, 2018Co-Authors: Ryo Tamura, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Toshinori Ueno, Kazuya Maeda, Takao MasakiAbstract:Transforming growth factor-β1 (TGF-β1) is a major mediator of Peritoneal Fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of Fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on Peritoneal Fibrosis in mice and in human Peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of Peritoneal dialysis (PD) patients. Murine Peritoneal Fibrosis was induced by intraPeritoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-β1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis.
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Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal-induced Peritoneal Fibrosis
PloS one, 2017Co-Authors: Kazuya Maeda, Takuo Nagai, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Toshinori Ueno, Takao MasakiAbstract:Activity of H3K9 histone methyltransferase G9a is reportedly induced by transforming growth factor-β1 (TGF-β1) and plays an important role in the progression of cancer and Fibrosis. In this study, we investigated whether inhibition of G9a-mediated H3K9 methylation attenuates Peritoneal Fibrosis in mice and human Peritoneal mesothelial cells (HPMCs). Nonadherent cells of Peritoneal dialysis (PD) patients were isolated from PD effluent to examine expression of G9a. Peritoneal Fibrosis was induced by Peritoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 3 weeks. BIX01294, a G9a inhibitor, was administered by subcutaneous injection. Effects of BIX01294 on MGO-induced pathological and functional changes in mice were evaluated by immunohistochemistry and a Peritoneal equilibration test. HPMCs were isolated from human omentum, and the inhibitory effect of BIX01294 on TGF-β1-induced fibrotic changes was investigated in the HPMCs by western blotting. G9a was upregulated in nonadherent cells of human PD effluent, the peritoneum of MGO-injected mice, and TGF-β1-stimulated HPMCs. BIX01294 significantly reduced the submesothelial zone thickness and cell density in MGO-injected mice. Immunohistochemical staining revealed that BIX01294 treatment decreased not only mono-methylation of H3K9 (H3K9me1), but also the number of mesenchymal cells, accumulation of collagen, and infiltration of monocytes. In addition to the pathological changes, BIX01294 reduced the level of TGF-β1 in Peritoneal fluid and improved Peritoneal functions. Furthermore, BIX01294 inhibited TGF-β1-induced fibrotic changes along with suppression of H3K9me1 in HPMCs. Therefore, inhibition of H3K9 methyltransferase G9a suppresses Peritoneal Fibrosis through a reduction of H3K9me1.
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Linagliptin Ameliorates Methylglyoxal-induced Peritoneal Fibrosis in Mice.
PloS one, 2016Co-Authors: Takuo Nagai, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Kensuke Sasaki, Toshinori Ueno, Takao MasakiAbstract:Recent studies have reported increases of methylglyoxal (MGO) in Peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of Peritoneal Fibrosis through production of transforming growth factor-β1 (TGF-β1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced Peritoneal Fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal Fibrosis was induced by daily intraPeritoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraPeritoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of α-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved Peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-β1 concentration in the Peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO-injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced Peritoneal Fibrosis.
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Mizoribine suppresses the progression of experimental Peritoneal Fibrosis in a rat model.
Nephron. Experimental nephrology, 2009Co-Authors: Shunsuke Takahashi, Shigehiro Doi, Ayumu Nakashima, Takao Masaki, Yoshihiko Taniguchi, Tetsuji Arakawa, Toru Kawai, Takafumi Ito, Nobuoki Kohno, Noriaki YoriokaAbstract:Background/Aims: Peritoneal Fibrosis is a serious complication of Peritoneal dialysis (PD). It has been reported that administration of mizoribine, an effective immunosuppressant, ameliorated renal Fibrosis in a rat model of unilateral ureteral obstruction. We therefore examined the effects of mizoribine in an experimental model of Peritoneal Fibrosis. Methods: 24 rats were given a daily intraPeritoneal injection of chlorhexidine gluconate and ethanol dissolved in saline. The rats were divided into three groups (n = 8 per group) that received either vehicle or mizoribine at a dose of 2 or 8 mg/kg once a day. 28 days after the start of the treatments the rats were sacrificed and Peritoneal tissue samples collected. Macrophage infiltration (ED1), myofibroblast accumulation (α-smooth muscle actin (SMA)) and expression of type III collagen, transforming growth factor (TGF)-β and monocyte chemotactic protein-1 (MCP-1) were examined by immunohistochemistry. Results: Mizoribine significantly suppressed submesothelial zone thickening and reduced macrophage infiltration. Mizoribine also reduced collagen III+ area and decreased the number of α-SMA+, TGF-β+ and MCP-1+ cells. The magnitude of the changes observed was dose-dependent. Conclusion: The administration of mizoribine prevented the progression of Peritoneal Fibrosis in this rat model. Mizoribine may represent a novel therapy for Peritoneal sclerosis in patients undergoing long-term PD.
Shougang Zhuang - One of the best experts on this subject based on the ideXlab platform.
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Peritoneal Fibrosis and epigenetic modulation.
Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis, 2020Co-Authors: Yi Wang, Shougang Zhuang, Yingfeng Shi, Min Tao, Na LiuAbstract:Peritoneal dialysis (PD) is an effective treatment for patients with end-stage renal disease. However, Peritoneal Fibrosis (PF) is a common complication that ultimately leads to ultrafiltration failure and discontinuation of PD after long-term PD therapy. There is currently no effective therapy to prevent or delay this pathologic process. Recent studies have reported epigenetic modifications involved in PF, and accumulating evidence suggests that epigenetic therapies may have the potential to prevent and treat PF clinically. The major epigenetic modifications in PF include DNA methylation, histone modification, and noncoding RNAs. The mechanisms of epigenetic regulation in PF are complex, predominantly involving modification of signaling molecules, transcriptional factors, and genes. This review will describe the mechanisms of epigenetic modulation in PF and discuss the possibility of targeting them to prevent and treat this complication.
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Delayed administration of suramin attenuates Peritoneal Fibrosis in rats.
BMC nephrology, 2019Co-Authors: Chongxiang Xiong, Na Liu, Xiaofei Shao, Sairah Sharif, Hequn Zou, Shougang ZhuangAbstract:Background Peritoneal Fibrosis is the most common complication of Peritoneal dialysis, but there is currently no effective treatment. We previously reported that suramin pretreatment prevents the development of Peritoneal Fibrosis in a rat model of Peritoneal Fibrosis induced by chlorhexidine gluconate (CG). Here, we further examined the effectiveness of delayed administration of suramin on Peritoneal Fibrosis and the mechanism (s) involved in this process.
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Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of Peritoneal Fibrosis.
The Journal of pathology, 2019Co-Authors: Yingfeng Shi, Shougang Zhuang, Yi Wang, Andong Qiu, Xiujuan Zang, Min Tao, Na LiuAbstract:Dysregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of many cancers. However, the role of EZH2 in Peritoneal Fibrosis remains unknown. We investigated EZH2 expression in Peritoneal dialysis (PD) patients and assessed its role in Peritoneal Fibrosis in cultured human Peritoneal mesothelial cells (HPMCs) and murine models of Peritoneal Fibrosis induced by chlorhexidine gluconate (CG) or high glucose Peritoneal dialysis fluid (PDF) by using 3-deazaneplanocin A (3-DZNeP), and EZH2 conditional knockout mice. An abundance of EZH2 was detected in the peritoneum of patients with PD associated peritonitis and the dialysis effluent of long-term PD patients, which was positively correlated with expression of TGF-β1, vascular endothelial growth factor, and IL-6. EZH2 was found highly expressed in the peritoneum of mice following injury by CG or PDF. In both mouse models, treatment with 3-DZNeP attenuated Peritoneal Fibrosis and inhibited activation of several profibrotic signaling pathways, including TGF-β1/Smad3, Notch1, epidermal growth factor receptor and Src. EZH2 inhibition also inhibited STAT3 and nuclear factor-κB phosphorylation, and reduced lymphocyte and macrophage infiltration and angiogenesis in the injured peritoneum. 3-DZNeP effectively improved high glucose PDF-associated Peritoneal dysfunction by decreasing the dialysate-to-plasma ratio of blood urea nitrogen and increasing the ratio of dialysate glucose at 2 h after PDF injection to initial dialysate glucose. Moreover, delayed administration of 3-DZNeP inhibited Peritoneal Fibrosis progression, reversed established Peritoneal Fibrosis and reduced expression of tissue inhibitor of metalloproteinase 2, and matrix metalloproteinase-2 and -9. Finally, EZH2-KO mice exhibited less Peritoneal Fibrosis than EZH2-WT mice. In HPMCs, treatment with EZH2 siRNA or 3-DZNeP suppressed TGF-β1-induced upregulation of α-SMA and Collagen I and preserved E-cadherin. These results indicate that EZH2 is a key epigenetic regulator that promotes Peritoneal Fibrosis. Targeting EZH2 may have the potential to prevent and treat Peritoneal Fibrosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Targeting Src attenuates Peritoneal Fibrosis and inhibits the epithelial to mesenchymal transition
Oncotarget, 2017Co-Authors: Jun Wang, Na Liu, Feng Liu, Li Wang, Yingfeng Shi, Shougang ZhuangAbstract:// Jun Wang 1 , Li Wang 1 , Liuqing Xu 1 , Yingfeng Shi 1 , Feng Liu 1 , Hualin Qi 1 , Na Liu 1 and Shougang Zhuang 1, 2 1 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China 2 Department of Medicine, Alpert Medical School and Rhode Island Hospital, Brown University, Providence, RI, USA Correspondence to: Shougang Zhuang, email: szhuang@lifespan.org Keywords: Src, Peritoneal Fibrosis, epithelial to mesenchymal transition, myofibroblasts, epidermal growth factor receptor Received: June 09, 2017 Accepted: July 25, 2017 Published: August 08, 2017 ABSTRACT Src has been reported to mediate tissue Fibrosis in several organs, but its role in Peritoneal Fibrosis remains unknown. In this study, we evaluated the therapeutic effect of KX2-391, a highly selective inhibitor of Src, on the development of Peritoneal Fibrosis in a rat model. Daily intraPeritoneal injections of chlorhexidine gluconate induced Peritoneal Fibrosis, as indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts. This was accompanied by time-dependent phosphorylation of Src at tyrosine 416. Administration of KX2-391 attenuated Peritoneal Fibrosis and abrogated increased phosphorylation of Src and multiple signaling molecules associated with tissue Fibrosis, including epidermal growth factor receptor, Akt, Signal transducer and activator of transcription 3 and nuclear factor-κB in the injured peritoneum. KX2-391 also inhibited the production of proinflammatory cytokines and the infiltration of macrophages into the injured peritoneum. In cultured human Peritoneal mesothelial cells, inhibition of Src by KX2-391 or siRNA resulted in decreased expression of α-smooth muscle actin (α-SMA), fibronectin and collagen I, the hallmarks of epithelial to mesenchymal transition. These results suggest that Src is a critical mediator of Peritoneal Fibrosis and the epithelial to mesenchymal transition. Thus, Src could be a potential therapeutic target in the treatment of Peritoneal Fibrosis.
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Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis
Journal of the American Society of Nephrology : JASN, 2015Co-Authors: Li Wang, Chongxiang Xiong, Na Liu, Yingfeng Shi, Andong Qiu, Xiujuan Zang, Haiping Mao, Shougang ZhuangAbstract:Inhibitors of EGF receptor (EGFR) have antifibrotic effects in several organs, but the effect of these inhibitors on the development of Peritoneal Fibrosis is unknown. Here, we explored the therapeutic effect of gefitinib, a specific inhibitor of EGFR, on the development and progression of Peritoneal Fibrosis in a rat model. Daily intraPeritoneal injections of chlorhexidine gluconate induced Peritoneal Fibrosis, indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts, accompanied by time-dependent phosphorylation of EGFR. Administration of gefitinib immediately after injury prevented the onset of Peritoneal Fibrosis and delayed administration after the onset of Peritoneal Fibrosis halted Fibrosis progression. Gefitinib treatment abrogated the increased phosphorylation of EGFR, Smad3, signal transducer and activator of transcription 3, and NF-κB during Peritoneal Fibrosis; it also inhibited the accompanying overproduction of TGF-β1 and proinflammatory cytokines and the infiltration of macrophages to the injured peritoneum. Moreover, gefitinib significantly reduced the Peritoneal increase of CD31-positive blood vessels and vascular EGF-positive cells after injury. Finally, gefitinib also attenuated high glucose-induced Peritoneal Fibrosis in rats and abrogated TGF-β1-induced phosphorylation of Smad3 and the epithelial-to-mesenchymal transition of cultured human Peritoneal mesothelial cells. These results demonstrate that EGFR contributes to Peritoneal Fibrosis, inflammation, and angiogenesis, suggesting that EGFR inhibitors may have therapeutic potential in attenuating Peritoneal Fibrosis.
Hui Y. Lan - One of the best experts on this subject based on the ideXlab platform.
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Opposing roles for Smad2 and Smad3 in Peritoneal Fibrosis in vivo and in vitro.
The American journal of pathology, 2014Co-Authors: Wen-juan Duan, Xiao-ru Huang, Hui Y. LanAbstract:Peritoneal Fibrosis is a major cause of ultrafiltration failure in patients receiving continuous ambulatory Peritoneal dialysis. Transforming growth factor (TGF)-β1 is an important mediator in this process; however, its signaling mechanisms had not been explored. Thus, we examined TGF-β1/Smad signaling in human Peritoneal biopsy specimens associated with continuous ambulatory Peritoneal dialysis. We found that TGF-β/Smad2/3 signaling was highly activated in patients with increased collagen deposition and thickening of the Peritoneal membrane who were receiving continuous ambulatory Peritoneal dialysis. Long-term exposure of wild-type mice to 4.25% Peritoneal dialysis solution for 30 days induced significant Peritoneal Fibrosis with impaired Peritoneal equilibrium, which was prevented in Smad3 knockout mice. In contrast, conditional Smad2 gene deletion in the peritoneum exacerbated Peritoneal Fibrosis and dysfunction. The contrasting roles of Smad2 and Smad3 in Peritoneal Fibrosis were also examined in vitro . Cultured mesothelial cells from Smad3 knockout mice were resistant to TGF-β1–induced collagen I production and the transition toward a myofibroblast phenotype as seen in wild-type cells, whereas Smad2 deficiency in mesothelial cells failed to modulate the profibrotic response to TGF-β1. In conclusion, this study found activation of TGF-β/Smad signaling in Peritoneal Fibrosis in patients receiving continuous ambulatory Peritoneal dialysis and identifies opposing roles for Smad2 and Smad3 in Peritoneal dialysis–associated Peritoneal Fibrosis. These findings provide a mechanistic basis for future therapies targeting TGF-β/Smad signaling in Peritoneal Fibrosis.
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Smad7 gene transfer inhibits Peritoneal Fibrosis.
Kidney international, 2007Co-Authors: Jing Nie, Xianrui Dou, Wenke Hao, Xin Wang, Wenxing Peng, Zhan-jun Jia, Wenfang Chen, Ning Luo, Hui Y. LanAbstract:Fibrosis mediated by transforming growth factor- β (TGF- β ) is a common cause of Peritoneal dialysis (PD) failure. In a model of Peritoneal Fibrosis, we tested the effect of Smad7, an inhibitor of TGF- β signaling, using an ultrasound-microbubble-mediated delivery system. Rats were given daily PD for 4 weeks and received Smad7 or control plasmid transfer. The ultrasound technique enhanced Smad7 expression in a dose-dependent manner in more than 80% of the Peritoneal cells after 3 days. The expression decreased by 14 days, but this was corrected by a second gene transfer. The overexpression of Smad7 substantially inhibited Smad2/3 activation, TGF- β , plasminogen activator inhibitor-1, extracellular matrix, and myofibroblast mRNA, and protein expression in the Peritoneal cells. The decreased Peritoneal injury included the rise of mass transfer of glucose, a reduction of the ultrafiltration rate, and fibrotic thickening. Our studies suggest that ultrasound-mediated Smad7 gene delivery may be useful in the prevention or treatment of dialysis-induced Peritoneal Fibrosis.
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Smad7 Transgene Attenuates Peritoneal Fibrosis in Uremic Rats Treated with Peritoneal Dialysis
Journal of the American Society of Nephrology : JASN, 2007Co-Authors: Hong Guo, Hui Y. Lan, Joseph Leung, Man Fai Lam, Loretta Y.y. Chan, Anita W. L. Tsang, Kar Neng LaiAbstract:Transforming growth factor β (TGF-β) plays a critical role in the pathogenesis of the Peritoneal Fibrosis that complicates long-term Peritoneal dialysis (PD). We studied the TGF-β/Smad signaling pathway in Peritoneal Fibrosis induced in uremic rats treated with PD and explored the therapeutic potential of Smad7 to prevent fibrogenesis. After subtotal nephrectomy, uremic rats were treated with Peritoneal dialysis using 4.25% dextrose-containing fluid. The peritoneum of uremic rats treated with PD demonstrated Fibrosis, increased TGF-β expression, increased Smad2/3 activation, decreased Smad7 expression, and increased expression of fibrogenic and angiogenic factors. In addition, Peritoneal function was impaired and its structure was altered, including a thickened submesothelial layer. In rats transfected with a Smad7 transgene using an ultrasound-microbubble–mediated system, Peritoneal Fibrosis was attenuated, Peritoneal function was improved, and Smad2/3 activation was inhibited. We suggest that administration of Smad7 inhibits Peritoneal fibrogenesis in uremic rats treated with PD by correcting the imbalance between downregulated Smad7 and activated Smad2/3. Blockade of the TGF-β/Smad signaling pathway may represent a novel therapeutic approach to prevent Peritoneal Fibrosis in patients treated with PD.
Ayumu Nakashima - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the h3k4 methyltransferase set7 9 ameliorates Peritoneal Fibrosis
PLOS ONE, 2018Co-Authors: Ryo Tamura, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Toshinori Ueno, Kazuya Maeda, Takao MasakiAbstract:Transforming growth factor-β1 (TGF-β1) is a major mediator of Peritoneal Fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of Fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on Peritoneal Fibrosis in mice and in human Peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of Peritoneal dialysis (PD) patients. Murine Peritoneal Fibrosis was induced by intraPeritoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-β1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis.
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Inhibition of the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis
PloS one, 2018Co-Authors: Ryo Tamura, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Toshinori Ueno, Kazuya Maeda, Takao MasakiAbstract:Transforming growth factor-β1 (TGF-β1) is a major mediator of Peritoneal Fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of Fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on Peritoneal Fibrosis in mice and in human Peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of Peritoneal dialysis (PD) patients. Murine Peritoneal Fibrosis was induced by intraPeritoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-β1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis.
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Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal-induced Peritoneal Fibrosis
PloS one, 2017Co-Authors: Kazuya Maeda, Takuo Nagai, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Toshinori Ueno, Takao MasakiAbstract:Activity of H3K9 histone methyltransferase G9a is reportedly induced by transforming growth factor-β1 (TGF-β1) and plays an important role in the progression of cancer and Fibrosis. In this study, we investigated whether inhibition of G9a-mediated H3K9 methylation attenuates Peritoneal Fibrosis in mice and human Peritoneal mesothelial cells (HPMCs). Nonadherent cells of Peritoneal dialysis (PD) patients were isolated from PD effluent to examine expression of G9a. Peritoneal Fibrosis was induced by Peritoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 3 weeks. BIX01294, a G9a inhibitor, was administered by subcutaneous injection. Effects of BIX01294 on MGO-induced pathological and functional changes in mice were evaluated by immunohistochemistry and a Peritoneal equilibration test. HPMCs were isolated from human omentum, and the inhibitory effect of BIX01294 on TGF-β1-induced fibrotic changes was investigated in the HPMCs by western blotting. G9a was upregulated in nonadherent cells of human PD effluent, the peritoneum of MGO-injected mice, and TGF-β1-stimulated HPMCs. BIX01294 significantly reduced the submesothelial zone thickness and cell density in MGO-injected mice. Immunohistochemical staining revealed that BIX01294 treatment decreased not only mono-methylation of H3K9 (H3K9me1), but also the number of mesenchymal cells, accumulation of collagen, and infiltration of monocytes. In addition to the pathological changes, BIX01294 reduced the level of TGF-β1 in Peritoneal fluid and improved Peritoneal functions. Furthermore, BIX01294 inhibited TGF-β1-induced fibrotic changes along with suppression of H3K9me1 in HPMCs. Therefore, inhibition of H3K9 methyltransferase G9a suppresses Peritoneal Fibrosis through a reduction of H3K9me1.
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Linagliptin Ameliorates Methylglyoxal-induced Peritoneal Fibrosis in Mice.
PloS one, 2016Co-Authors: Takuo Nagai, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Kensuke Sasaki, Toshinori Ueno, Takao MasakiAbstract:Recent studies have reported increases of methylglyoxal (MGO) in Peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of Peritoneal Fibrosis through production of transforming growth factor-β1 (TGF-β1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced Peritoneal Fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal Fibrosis was induced by daily intraPeritoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraPeritoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of α-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved Peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-β1 concentration in the Peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO-injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced Peritoneal Fibrosis.
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Mizoribine suppresses the progression of experimental Peritoneal Fibrosis in a rat model.
Nephron. Experimental nephrology, 2009Co-Authors: Shunsuke Takahashi, Shigehiro Doi, Ayumu Nakashima, Takao Masaki, Yoshihiko Taniguchi, Tetsuji Arakawa, Toru Kawai, Takafumi Ito, Nobuoki Kohno, Noriaki YoriokaAbstract:Background/Aims: Peritoneal Fibrosis is a serious complication of Peritoneal dialysis (PD). It has been reported that administration of mizoribine, an effective immunosuppressant, ameliorated renal Fibrosis in a rat model of unilateral ureteral obstruction. We therefore examined the effects of mizoribine in an experimental model of Peritoneal Fibrosis. Methods: 24 rats were given a daily intraPeritoneal injection of chlorhexidine gluconate and ethanol dissolved in saline. The rats were divided into three groups (n = 8 per group) that received either vehicle or mizoribine at a dose of 2 or 8 mg/kg once a day. 28 days after the start of the treatments the rats were sacrificed and Peritoneal tissue samples collected. Macrophage infiltration (ED1), myofibroblast accumulation (α-smooth muscle actin (SMA)) and expression of type III collagen, transforming growth factor (TGF)-β and monocyte chemotactic protein-1 (MCP-1) were examined by immunohistochemistry. Results: Mizoribine significantly suppressed submesothelial zone thickening and reduced macrophage infiltration. Mizoribine also reduced collagen III+ area and decreased the number of α-SMA+, TGF-β+ and MCP-1+ cells. The magnitude of the changes observed was dose-dependent. Conclusion: The administration of mizoribine prevented the progression of Peritoneal Fibrosis in this rat model. Mizoribine may represent a novel therapy for Peritoneal sclerosis in patients undergoing long-term PD.
Shigehiro Doi - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the h3k4 methyltransferase set7 9 ameliorates Peritoneal Fibrosis
PLOS ONE, 2018Co-Authors: Ryo Tamura, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Toshinori Ueno, Kazuya Maeda, Takao MasakiAbstract:Transforming growth factor-β1 (TGF-β1) is a major mediator of Peritoneal Fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of Fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on Peritoneal Fibrosis in mice and in human Peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of Peritoneal dialysis (PD) patients. Murine Peritoneal Fibrosis was induced by intraPeritoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-β1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis.
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Inhibition of the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis
PloS one, 2018Co-Authors: Ryo Tamura, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Toshinori Ueno, Kazuya Maeda, Takao MasakiAbstract:Transforming growth factor-β1 (TGF-β1) is a major mediator of Peritoneal Fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of Fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on Peritoneal Fibrosis in mice and in human Peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of Peritoneal dialysis (PD) patients. Murine Peritoneal Fibrosis was induced by intraPeritoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-β1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates Peritoneal Fibrosis.
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Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal-induced Peritoneal Fibrosis
PloS one, 2017Co-Authors: Kazuya Maeda, Takuo Nagai, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Toshinori Ueno, Takao MasakiAbstract:Activity of H3K9 histone methyltransferase G9a is reportedly induced by transforming growth factor-β1 (TGF-β1) and plays an important role in the progression of cancer and Fibrosis. In this study, we investigated whether inhibition of G9a-mediated H3K9 methylation attenuates Peritoneal Fibrosis in mice and human Peritoneal mesothelial cells (HPMCs). Nonadherent cells of Peritoneal dialysis (PD) patients were isolated from PD effluent to examine expression of G9a. Peritoneal Fibrosis was induced by Peritoneal injection of methylglyoxal (MGO) in male C57/B6 mice for 3 weeks. BIX01294, a G9a inhibitor, was administered by subcutaneous injection. Effects of BIX01294 on MGO-induced pathological and functional changes in mice were evaluated by immunohistochemistry and a Peritoneal equilibration test. HPMCs were isolated from human omentum, and the inhibitory effect of BIX01294 on TGF-β1-induced fibrotic changes was investigated in the HPMCs by western blotting. G9a was upregulated in nonadherent cells of human PD effluent, the peritoneum of MGO-injected mice, and TGF-β1-stimulated HPMCs. BIX01294 significantly reduced the submesothelial zone thickness and cell density in MGO-injected mice. Immunohistochemical staining revealed that BIX01294 treatment decreased not only mono-methylation of H3K9 (H3K9me1), but also the number of mesenchymal cells, accumulation of collagen, and infiltration of monocytes. In addition to the pathological changes, BIX01294 reduced the level of TGF-β1 in Peritoneal fluid and improved Peritoneal functions. Furthermore, BIX01294 inhibited TGF-β1-induced fibrotic changes along with suppression of H3K9me1 in HPMCs. Therefore, inhibition of H3K9 methyltransferase G9a suppresses Peritoneal Fibrosis through a reduction of H3K9me1.
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Linagliptin Ameliorates Methylglyoxal-induced Peritoneal Fibrosis in Mice.
PloS one, 2016Co-Authors: Takuo Nagai, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Kensuke Sasaki, Toshinori Ueno, Takao MasakiAbstract:Recent studies have reported increases of methylglyoxal (MGO) in Peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of Peritoneal Fibrosis through production of transforming growth factor-β1 (TGF-β1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced Peritoneal Fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal Fibrosis was induced by daily intraPeritoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraPeritoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of α-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved Peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-β1 concentration in the Peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO-injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced Peritoneal Fibrosis.
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Mizoribine suppresses the progression of experimental Peritoneal Fibrosis in a rat model.
Nephron. Experimental nephrology, 2009Co-Authors: Shunsuke Takahashi, Shigehiro Doi, Ayumu Nakashima, Takao Masaki, Yoshihiko Taniguchi, Tetsuji Arakawa, Toru Kawai, Takafumi Ito, Nobuoki Kohno, Noriaki YoriokaAbstract:Background/Aims: Peritoneal Fibrosis is a serious complication of Peritoneal dialysis (PD). It has been reported that administration of mizoribine, an effective immunosuppressant, ameliorated renal Fibrosis in a rat model of unilateral ureteral obstruction. We therefore examined the effects of mizoribine in an experimental model of Peritoneal Fibrosis. Methods: 24 rats were given a daily intraPeritoneal injection of chlorhexidine gluconate and ethanol dissolved in saline. The rats were divided into three groups (n = 8 per group) that received either vehicle or mizoribine at a dose of 2 or 8 mg/kg once a day. 28 days after the start of the treatments the rats were sacrificed and Peritoneal tissue samples collected. Macrophage infiltration (ED1), myofibroblast accumulation (α-smooth muscle actin (SMA)) and expression of type III collagen, transforming growth factor (TGF)-β and monocyte chemotactic protein-1 (MCP-1) were examined by immunohistochemistry. Results: Mizoribine significantly suppressed submesothelial zone thickening and reduced macrophage infiltration. Mizoribine also reduced collagen III+ area and decreased the number of α-SMA+, TGF-β+ and MCP-1+ cells. The magnitude of the changes observed was dose-dependent. Conclusion: The administration of mizoribine prevented the progression of Peritoneal Fibrosis in this rat model. Mizoribine may represent a novel therapy for Peritoneal sclerosis in patients undergoing long-term PD.