Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression
| Autor: | Monica V. Masucci, Evelyn Tolbert, Ting C. Zhao, Xiujuan Zang, Na Liu, Shougang Zhuang, Murugavel Ponnusamy, George Bayliss, Xiaoxu Zhou, Rujun Gong, Lance D. Dworkin |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male macromolecular substances urologic and male genital diseases Kidney Smad7 Protein 03 medical and health sciences Mice Transforming Growth Factor beta medicine Renal fibrosis Tensin PTEN Animals Enhancer of Zeste Homolog 2 Protein biology Errata EZH2 PTEN Phosphohydrolase General Medicine Transforming growth factor beta Fibroblasts Fibrosis 030104 developmental biology medicine.anatomical_structure Nephrology Cancer research biology.protein Phosphorylation Kidney Diseases Signal transduction |
| Zdroj: | Journal of the American Society of Nephrology : JASN. 27(7) |
| ISSN: | 1533-3450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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