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EZH2 plays a crucial role in ischemia/reperfusion-induced acute kidney injury by regulating p38 signaling.
Inflamm Res ; 68(4): 325-336, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820607


Renal ischemia-reperfusion (IR)-induced acute kidney injury (AKI) remains a major challenge in clinic. The histone methyltransferases enhancer of zest homolog-2 (EZH2) is associated with the development of renal injury. However, the molecular mechanism has not been fully elucidated.MATERIALS: AKI in C57BL/6 mice was generated by renal IR.TREATMENTS: The 3-deazaneplanocin A (DZNeP), a selective EZH2 inhibitor, or vehicle was administrated in mice after IR. HK-2 cells were exposed to hypoxia-reoxygenation (H/R) stress.


Apoptosis was detected by TUNEL assay or flow cytometry. EZH2, caspase-3, p38, F4/80+ macrophages, and CD3+ T cells were examined by immunohistochemistry or Western blot. Tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, IL-6, and IL-18 were measured using RT-PCR.


Mice treated with DZNeP exhibited less severe renal dysfunction and tubular injury following IR. EZH2 inhibition decreased apoptotic cells while reducing activation of caspase-3 in kidneys under IR condition. Moreover, EZH2 inhibition impaired the recruitment of CD3+ T cells and F4/80+ cells in kidneys with IR. Administration of DZNeP suppressed the production of TNF-α, MCP-1, IL-6, and IL-18 in IR-treated kidneys. Of note, EZH2 inhibition reduced p38 phosphorylation in kidneys after IR. In H/R-treated HK-2 cells, DZNeP treatment or EZH2 knockdown reduced apoptosis. EZH2 inhibition inactivated p38 resulting in reduction of active caspase-3 and proinflammatory molecules. By contrast, EZH2 overexpression induced p38 phosphorylation, caspase-3 activation, and production of proinflammatory molecules, which was reversed by SB203580.


EZH2 plays a crucial role in IR-induced AKI via modulation of p38 signaling. Targeting EZH2/p38 signaling pathway may offer novel strategies to protect kidneys from acute kidney injury induced by ischemia-reperfusion.





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Traumatismo por Reperfusão / Proteínas Quinases p38 Ativadas por Mitógeno / Lesão Renal Aguda / Proteína Potenciadora do Homólogo 2 de Zeste Limite: Animais / Humanos / Masculino Idioma: Inglês Revista: Inflamm Res Assunto da revista: Alergia e Imunologia / Patologia Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: China