Inhibition of the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis

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.

Peritoneal fibrosis and epigenetic modulation

“…One year later, this research team reaffirmed the importance of histone methylation in PF by identifying new methylation sites, H3K4 mono-methylation (H3K4me1) associated with the methyltransferase, SET7/9. 52 They found that SET7/9 expression was significantly upregulated in MCs isolated from the PD effluent of PD patients and positively correlated with D/P creatinine ratio. They showed that sinefungin, a specific inhibitor of SET7/9, not only suppressed both cellularity and thickening of the submesothelial compact zone but also improved peritoneal function including the urea nitrogen transport rate from plasma and the glucose absorption rate from dialysate compared with the control mice.…”

“…Histone methylation has been confirmed to be involved in multiple fibrotic diseases, including lung fibrosis, 48 cardiac fibrosis, 49 kidney fibrosis, 50 and PF. 51,52 Maeda et al, whose study focused on H3K9 histone methyltransferase G9a, found elevation of G9a expression levels in nonadherent cells of human PD effluent. Meanwhile, they established a PF animal model induced by peritoneal injection of methylglyoxal in male C57/B6 mice.…”

Elevated expression of HDAC6 in clinical peritoneal dialysis patients and its pathogenic role on peritoneal angiogenesis

“…So, expression levels of these biomolecules can be used as predicted biomarkers to estimate the progression of peritoneal injury for long-term PD patients to a certain extent. Recently, it has been demonstrated that epigenetic enzyme can regulate the progression of PF by modifying a series of signaling pathway proteins and transcription factors [ 14 , 24 , 25 ].…”

Histone Methyltransferases as Therapeutic Targets for Kidney Diseases

“…These studies provide evidence for the involvement of SET7/9 in renal fibrosis. Sasaki et al (2016) reported that SET7/9 expression was also increased in the peritoneum in a murine model of peritoneal fibrosis induced by methylglyoxal and as well as in non-adherent cells isolated from the effluent of PD patients; treatment with sinefungin inhibited expression of collagen deposition in the peritoneum and improved peritoneal function, which is accompanied by decreased expression of H3K4me1 as well (Tamura et al, 2018).…”

“…Sinefungin is a small molecule inhibitor of SET7/9 that acts by competing with S-adenosyl-L-methionine and can ameliorate renal fibrosis (Sasaki et al, 2016) and peritoneal fibrosis (Tamura et al, 2018) in animal models. However, sinefungin treatment significantly reduced expression of H3K4me1, but did not alter expression of H3K4me2 and H3K4me3 in the kidneys of UUO mice.…”