肾内类淋巴组织样结构(TLO)形成是肾间质纤维化启动阶段重要的组织学事件,是炎症-组织损伤-肾脏纤维化恶性循环的驱动者。申请者发现:肾间质内高内皮微静脉(HEV)新生与TLO形成密切相关。而HEV功能又与HEV表型特点有关,受树突状细胞(DC)调控。申请者既往还发现:Semaphorin 4C(Sema4C)在损伤后的肾小管上皮高表达,是肾间质纤维化重要的调控分子。近期其他学者发现:Sema4C表达于HEV内皮细胞;其配体Plexin-B2表达于HEV内皮细胞和DC,参与调控血管生成和DC活化。可见:Sema4C/Plexin-B2具备调控HEV新生和表型特点的潜能。本项目拟从临床、动物、细胞三个层面,结合CD11c-DTR转基因小鼠的应用和TELANs基因靶向修饰技术,阐明Sema4C/Plexin-B2通路调控HEV介导的TLO形成的机制,为探索肾间质纤维化防治新策略提供实验依据。

Tertiary lymphoid organs (TLO) neogenesis is one of the most important histological events in the priming phase of renal interstitial fibrosis, which is a relentless driver of the vicious cycle of inflammation, tissue damage and fibrosis. Our previous data have showed that high endothelial venules (HEV) development in renal interstitial area is closely related with lymphoid neogenesis. And the phenotypic characteristics of HEV, which is regulated by dendritic cells (DC), are also involved in HEV-mediated lymphocyte homing. Our past studies have found that semaphorin 4C (Sema4C) expression is upregulated in injured renal tubular epithelial cells and plays an important role in progressive renal interstitial fibrosis. Recently other researchers have detected that Sema4C is expressed in HEV endothelial cells, and its ligand, Plexin-B2, is expressed in both HEV endothelial cells and DC, which is involved in the regulation of angiogenesis and DC activity. Therefore Sema4C/Plexin-B2 signaling pathway is thought to have the potential to regulate HEV neogenesis and phenotypic conversion. In this project, we will plan to clarify the mechanisms of HEV-mediated TLO neogenesis via Sema4C/Plexin-B2 signaling pathway and explore the new preventive and therapeutic strategy in the early stage of renal fibrosis by using CD11c-DTR mice for DC deletion and transcription activator-like effectors nucleases (TALENs) technique for targeted gene editing.