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EZH2 (enhancer of zestehomolog 2) is a methyltransferase that induces histone H3 lysine 27 tfimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types.However, its rolein renal fibrogenesis remains to be explored.In this study, we found that EZH2 and H3K27me3 were highly expressed in the cultured renal fibroblastsand thefibrotic kidney from mice with unilateral ureteral obstruction and from humans withchronic kidney disease.Pharmacological inhibition of EZH2 with3deazaneplanocin A(3DZNeP) and GSK126, or silencing of EZH2 with its specific siRNA, inhibited serumand TGFβ1induced activation of renal interstitial fibroblasts in vitro, and 3DZNeP administration abrogated deposition of extracellular matrix proteins and expression of αSMA in the obstructed kidney.Mechanistically,3DZNeP inhibited expression of type Ⅰ TGFβ1 receptor and phosphorylation of Smad3, along with preservation of Smad7 expression.3DZNeP treatment also suppressed phosphorylation of the EGF and PDGFβ receptors as well as STAT3 and ERK1/2, two signaling pathways associated with renal fibrosis in the injured kidney.Moreover, EZH2 inhibition increased expression of PTEN, a protein tyrosine phosphatase associated with the dephosphorylation of multiple tyrosine kinase receptors, in the kidney after ureteral ligation and in serumstimulated renal interstitial fibroblasts.Finally, inhibition of PTEN reversed the antagonistic effect of3DZNeP on myofibroblast activation.These results uncovered the important role of EZH2in mediating activation of renal fibroblasts and the development of renal fibrosis through the activation of multiple profibrotic signaling pathways.Targeted inhibition of EZH2 could therefore represent a novel therapy to treat chronic kidney disease.