title: Inhibition of histone methyltransferase EZH2 ameliorates early acute renal allograft rejection in rats.
abstract: Although histone methyltransferases EZH2 has been proved to have significant regulatory effect on the immune rejection after hematopoietic stem cell transplantation, its role in solid-organ transplantation remains uncovered. In this study, we investigate whether histone methylation regulation can impact renal allograft rejection in rat models.
  
  
  
  Allogeneic rat renal transplantation model (Wistar to Lewis) was established, and the recipients were administrated with EZH2 inhibitor DZNep after transplantation. Renal allografts and peripheral blood were collected on day 5 after transplantation for histological examination and mechanism investigation. We found that inhibition of EZH2 by DZNep after transplantation significantly ameliorated acute rejection (AR), with decreased histological injury and reduced inflammatory infiltration in renal allografts. Attenuation of AR was due to the prohibited activation of alloreactive T cells, the subsequent impaired production of inflammatory cytokines, and also the elevated apoptosis of alloreactive T cells in both renal allografts and periphery. However, inhibition of EZH2 did not increase the regulatory T cells during the AR.
  
  
  
  Disruption of EZH2 by DZNep suppressed the immune responses of alloreactive T cells and ameliorated AR of renal allografts. This suggests a therapeutic potential of targeting histone methyltransferases EZH2 in treating allograft rejection after solid organ transplantation.
authors: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.
authors: Long
authors: L
authors: Li
authors: Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.|Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.
authors: Ming
authors: M
authors: Xu
authors: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.
authors: Ruiming
authors: R
authors: Rong
authors: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. wang.jina@zs-hospital.sh.cn.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. wang.jina@zs-hospital.sh.cn.
authors: Jina
authors: J
authors: Wang
authors: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. tyzhu_dr@163.com.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. tyzhu_dr@163.com.
authors: Tongyu
authors: T
authors: Zhu
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D058990:Molecular Targeted Therapy; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D006657:Histones; D018836:Inflammation Mediators; C578253:EZH2 protein, rat; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: Acute rejection; DZNep; EZH2; Epigenetic regulation; Renal transplantation