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Blockade of enhancer of zeste homolog 2 alleviates renal injury associated with hyperuricemia.
Shi, Yingfeng; Xu, Liuqing; Tao, Min; Fang, Lu; Lu, Jiasun; Gu, Hongwei; Ma, Shuchen; Lin, Tao; Wang, Yi; Bao, Wenfang; Qiu, Andong; Zhuang, Shougang; Liu, Na.
Afiliação
  • Shi Y; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Xu L; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Tao M; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Fang L; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Lu J; Department of Urology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Gu H; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Ma S; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Lin T; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Wang Y; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Bao W; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Qiu A; School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University , Shanghai , China.
  • Zhuang S; Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine , Shanghai , China.
  • Liu N; Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University , Providence, Rhode Island.
Am J Physiol Renal Physiol ; 316(3): F488-F505, 2019 03 01.
Article em En | MEDLINE | ID: mdl-30566000
Hyperuricemia has been identified as an independent risk factor for chronic kidney disease (CKD) and is associated with the progression of kidney diseases. It remains unknown whether enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, can regulate metabolism of serum uric acid and progression of renal injury induced by hyperuricemia. In this study, we demonstrated that blockade of EZH2 with 3-DZNeP, a selective EZH2 inhibitor, or silencing of EZH2 with siRNA inhibited uric acid-induced renal fibroblast activation and phosphorylation of Smad3, epidermal growth factor receptor (EGFR), and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in cultured renal fibroblasts. Inhibition of EZH2 also suppressed proliferation of renal fibroblasts and epithelial-mesenchymal transition of tubular cells. In a mouse model of renal injury induced by hyperuricemia, EZH2 and trimethylation of histone H3 at lysine27 expression levels were enhanced, which was coincident with renal damage and increased expression of lipocalin-2 and cleaved caspase-3. Inhibition of EZH2 with 3-DZNeP blocked all these responses. Furthermore, 3-DZNeP treatment decreased the level of serum uric acid and xanthine oxidase activity, alleviated renal interstitial fibrosis, inhibited activation of transforming growth factor-ß/Smad3, EGFR/ERK1/2, and nuclear factor-κB signaling pathways, as well as reduced expression of multiple chemokines/cytokines. Collectively, EZH2 inhibition can reduce the level of serum uric acid and alleviate renal injury and fibrosis through a mechanism associated with inhibition of multiple signaling pathways. Targeting EZH2 may be a novel strategy for the treatment of hyperuricemia-induced CKD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hiperuricemia / Fibroblastos / Proteína Potenciadora do Homólogo 2 de Zeste / Nefropatias Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Revista: Am J Physiol Renal Physiol Assunto da revista: FISIOLOGIA / NEFROLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: China País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hiperuricemia / Fibroblastos / Proteína Potenciadora do Homólogo 2 de Zeste / Nefropatias Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Revista: Am J Physiol Renal Physiol Assunto da revista: FISIOLOGIA / NEFROLOGIA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: China País de publicação: Estados Unidos