title: Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression.
abstract: Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. However, the role of EZH2 in renal fibrogenesis remains unexplored. In this study, we found high expression of EZH2 and H3K27me3 in cultured renal fibroblasts and fibrotic kidneys from mice with unilateral ureteral obstruction and humans with CKD. Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) or GSK126 or siRNA-mediated silencing of EZH2 inhibited serum- and TGFβ1-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of α-smooth muscle actin in the obstructed kidney. Injury to the kidney enhanced Smad7 degradation, Smad3 phosphorylation, and TGFβ receptor 1 expression, and 3-DZNeP administration prevented these effects. 3-DZNeP also suppressed phosphorylation of the renal EGF and PDGFβ receptors and downstream signaling molecules signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 after injury. Moreover, EZH2 inhibition increased the expression of phosphatase and tensin homolog (PTEN), a protein previously associated with dephosphorylation of tyrosine kinase receptors in the injured kidney and serum-stimulated renal interstitial fibroblasts. Finally, blocking PTEN with SF1670 largely diminished the inhibitory effect of 3-DZNeP on renal myofibroblast activation. These results uncovered the important role of EZH2 in mediating the development of renal fibrosis by downregulating expression of Smad7 and PTEN, thus activating profibrotic signaling pathways. Targeted inhibition of EZH2, therefore, could be a novel therapy for treating CKD.
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island; Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, China;
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island; Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, China;
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Zang
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Murugavel
authors.initials: M
authors.lastname: Ponnusamy
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Monica V
authors.initials: MV
authors.lastname: Masucci
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tolbert
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.affiliation: Department of Surgery, Boston University Medical School, Roger Williams Medical Center, Boston University, Providence, Rhode Island; and.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: George
authors.initials: G
authors.lastname: Bayliss
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Lance D
authors.initials: LD
authors.lastname: Dworkin
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China szhuang@lifespan.org.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000517:prevention & control; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D051906:Smad7 Protein / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D000071221:Enhancer of Zeste Homolog 2 Protein; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: chronic kidney disease; fibroblast; fibrosis; obstructive nephropathy; signaling