Inhibition of H3K9 methyltransferase G9a ameliorates methylglyoxal-induced peritoneal fibrosis

Maeda, Kazuya; Doi, Shigehiro; Nakashima, Ayumu; Nagai, Takuo; Irifuku, Taisuke; Ueno, Toshinori; Takao, Masaki

doi:10.1371/journal.pone.0173706

Cited by 18 publications

(14 citation statements)

References 34 publications

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“…In this study, inhibition of SET7/9 suppressed peritoneal fibrosis without changing TGF-β1 expression in MGO-injected mice. Since our previous studies showed that TGF-β1 is co-expressed with inflammatory cells in a mouse model of MGO-induced peritoneal fibrosis [ 39 ], the present data imply that H3K4me1 does not affect inflammation.…”

Section: Discussionsupporting

confidence: 48%

“…Yang et al also reported that C646, a histone acetyltransferase inhibitor attenuates peritoneal fibrosis by blocking the TGF-β1/Smad3 signaling pathway [ 38 ]. Furthermore, we previously showed that the H3K9 methyltransferase G9a is implicated in peritoneal fibrosis [ 39 ]. These findings suggest that histone modification could be a therapeutic target during peritoneal fibrosis development.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis

et al. 2018

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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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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Inhibition of the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis

et al. 2018

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“…These pro-fibrotic changes both in vitro and in vivo were abrogated by application of the selective G9a-methyltransferase inhibitor BIX01294, with a reduction in repressive H3K9me1 levels (145). Similar therapeutic benefit through H3K9me1 suppression by G9a-methyltransferase inhibition has been also recently described in an in vitro model of peritoneal fibrosis (201). Involvement of G9a in gene repression has also been reported in pulmonary fibrosis through H3K9 trimethylation of the anti-fibrogenic cyclooxygenase-2 (COX2) gene promoter (69).…”

Section: Histone Methylation In Fibroblastsmentioning

confidence: 54%

Epigenetics of Aberrant Cardiac Wound Healing

Russell‐Hallinan

Watson

Baugh

2018

Comprehensive Physiology

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Remodeling of cardiac tissue architecture is essential for normal organ development and maintaining homeostasis after injury. Injurious insults to the heart, such as hypertension and myocardial infarction, promote cellular responses including stimulation of resident inflammatory cells, activation of endothelial cells and recruitment of immune cells, hypertrophy of cardiomyocytes, and activation of fibroblasts. The physiological goal of this coordinated cellular response is to repair damaged tissue while maintaining or restoring cardiac contractile function. Persistent uncontrolled inflammation, hypertrophy, and fibrosis in the heart due to hyperactive wound healing are detrimental and impair cardiac performance, facilitating the progression to heart failure. Abnormal changes in gene expression promote acquisition of aberrant cellular phenotypes that drive cardiac remodeling. DNA methylation and histone modifications are epigenetic mechanisms that critically regulate chromatin structure and gene expression, and are essential for normal physiology and development. Increasing clinical and experimental evidence suggests that these epigenetic mechanisms are involved in driving aberrant wound healing and the development of heart failure. While most of our knowledge to date is on the heart as a whole, the precise contribution of DNA methylation and histone modifications in regulating aberrant cardiac remodeling at the cellular level is less defined. Therefore, this overview aims to summarize the role of DNA methylation and histone modifications (acetylation and methylation) in heart failure and to comprehensively dissect the role these mechanisms play in regulating the function of cardiomyocytes, fibroblasts, and immune cells in response to injury. © 2018 American Physiological Society. Compr Physiol 8:451-491, 2018.

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“…Consistent with these observations, bleomycin-treated lungs showed a significant increase in hydroxyproline content, which was partially but not significantly reduced in the lungs of BIX01294-treated mice ( Figure 8G). These latest observations, while failing to reach statistical significance, are supported by recent papers reporting the beneficial effects of BIX01294 in mouse models of kidney and peritoneal fibrosis (60,61).…”

Section: Inhibition Of G9a Restores Ppargc1a Gene Expression In Vivo mentioning

confidence: 92%