Inhibition of the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis

Ryo Tamura,Kensuke Sasaki,Toshinori Ueno,Ayumu Nakashima,Takao Masaki,Kazuya Maeda,Shigehiro Doi,Philip C Trackman

doi:10.1371/journal.pone.0196844

Ryo Tamura, Kensuke Sasaki + Show 6 more

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https://doi.org/10.1371/journal.pone.0196844

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Journal: PloS one	Publication Date: May 3, 2018
Citations: 30	License type: CC BY 4.0

Affiliation: Hiroshima University Hospital

Abstract

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.

Highlights

Peritoneal dialysis (PD) has been used as an effective replacement therapy for patients with end-stage kidney disease
We found that SET domain-containing lysine methyltransferase 7/9 (SET7/9) expression was significantly upregulated in PD patients compared with human peritoneal mesothelial cells (HPMCs) from non-PD patients (Fig 1C and 1D)
We have demonstrated that sinefungin, a specific inhibitor of SET7/9, ameliorates peritoneal fibrosis and peritoneal dysfunction through suppression of H3K4me1

Summary

Introduction

Peritoneal dialysis (PD) has been used as an effective replacement therapy for patients with end-stage kidney disease. Long-term exposure to PD fluid leads to peritoneal fibrosis, which is clinically observed as the failure of fluid removal [1,2,3]. The pathogenesis of peritoneal fibrosis is characterized by loss of mesothelial cells with proliferation of α-smooth muscle actin (α-SMA)-positive myofibroblasts and deposition of extracellular matrix (ECM) proteins in submesothelial areas [4,5,6,7]. A number of cytokines reportedly participate in this process, transforming growth factor-β1 (TGF-β1) is considered to play a central role in the progression of peritoneal fibrosis [8,9,10].

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