title: Inhibition of SET Domain-Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis.
abstract: TGF-β1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain-containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-β1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-β1 neutralizing antibody. TGF-β1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P<0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-β1-induced α-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent.
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan sdoi@hiroshima-u.ac.jp masakit@hiroshima-u.ac.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Doi
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Nakashima
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Irifuku
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kokoroishi
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Doi
authors.affiliation: Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Hida
authors.affiliation: Department of Pathology, Hiroshima University Hospital, Hiroshima, Japan; and.
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
authors.affiliation: Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan sdoi@hiroshima-u.ac.jp masakit@hiroshima-u.ac.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000502:physiology; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D053773:Transforming Growth Factor beta1; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human
keywords: TGF-β; cell signaling; obstructive nephropathy; renal fibrosis