Department of Kidney Transplantation & Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China.
Shanghai Center for Drug Evaluation & Inspection, Shanghai 201203, China.
Exp Cell Res. 2019 Feb 15;375(2):20-27. doi: 10.1016/j.yexcr.2019.01.008. Epub 2019 Jan 9.
Antibody-mediated rejection (AMR) can cause graft loss and reduces long-term graft survival after kidney transplantation. Human leukocyte antigen (HLA) and/or non-HLA antibodies play a key role in the pathogenesis of AMR by targeting the allograft epithelium via complement activation and complement-independent mechanisms. However, the precise mechanisms of AMR remain unclear and treatment is still limited.
In this study, we investigated the role of the endothelial-associated transcription factor Sox7 in AMR, using the anti-HLA antibody W6/32, shRNA-mediated Sox7 knockdown, and by manipulating the Notch pathway. We used an in vitro human kidney glomerular endothelial cells (HKGECs) model and an in vivo MHC-mismatched kidney transplantation model.
Sox7 expression was upregulated and the Jagged1-Notch1 pathway was activated in HKGECs after W6/32 activation. W6/32 antibodies increased the expression of adhesion molecules (VCAM-1, ICAM-1), inflammatory cytokines (IL-6, TNF-α), and chemokines (CXCL8, CXCL10), and Sox7 knockdown and inhibition of the Notch pathway by DAPT significantly reduced these effects. Jagged1 overexpression rescued the inhibitory effects of Sox7 knockdown. In addition, Sox7 knockdown attenuated acute allograft kidney injury in mice and reduced the expression of adhesion molecules and Jagged1-Notch1 signaling after transplantation.
Our findings suggest that Sox7 plays an important role in mediating HLA I antibody-dependent endothelial cell activation and acute kidney allograft rejection via the Jagged1-Notch1 pathway. Manipulating Sox7 in donor organs may represent a useful treatment for AMR in solid organ transplantation.
抗体介导的排斥反应（AMR）可导致移植物丢失，并降低肾移植后的长期移植物存活率。人类白细胞抗原（HLA）和/或非 HLA 抗体通过补体激活和补体非依赖机制靶向同种异体上皮细胞，在 AMR 的发病机制中发挥关键作用。然而，AMR 的确切机制仍不清楚，治疗仍然有限。
在这项研究中，我们使用抗 HLA 抗体 W6/32、shRNA 介导的 Sox7 敲低和操纵 Notch 通路，研究了内皮相关转录因子 Sox7 在 AMR 中的作用。我们使用体外人肾脏肾小球内皮细胞（HKGEC）模型和体内 MHC 错配肾移植模型。
W6/32 激活后，HKGECs 中 Sox7 表达上调，Jagged1-Notch1 通路被激活。W6/32 抗体增加了粘附分子（VCAM-1、ICAM-1）、炎症细胞因子（IL-6、TNF-α）和趋化因子（CXCL8、CXCL10）的表达，而 Sox7 敲低和 DAPT 抑制 Notch 通路显著降低了这些作用。Jagged1 过表达挽救了 Sox7 敲低的抑制作用。此外，Sox7 敲低减轻了小鼠急性同种异体肾损伤，并降低了移植后粘附分子和 Jagged1-Notch1 信号的表达。
我们的研究结果表明，Sox7 通过 Jagged1-Notch1 通路在介导 HLA I 抗体依赖性内皮细胞激活和急性肾移植排斥反应中发挥重要作用。在供体器官中操纵 Sox7 可能代表实体器官移植中 AMR 的一种有用治疗方法。
