TNFSF14/HIF通路对AKI-to-CKD进展中肾间质管周毛细血管网毁损的作用及机制研究

Renal ischemia, hypoxia and inflammation are very important mechanism for the progress of acute kidney injury (AKI) to chronic kidney disease (CKD). Renal interstitial peritubular capillary network damage plays a crucial role during the disease progression. However, its mechanism is still not clear. Our group found that tumor necrosis factor superfamily 14 (TNFSF14) can cause human microvascular endothelial cells inflammation, stimulating HIF transcription through NF-κB pathway and it can also regulate vasoactive factors gene expression, encoding many vasoactive protein, leading to kidney damage and disease development. Thus, we propose a hypothesis: TNFSF14 possibly play an important role on renal interstitial peritubular capillary endothelial cell through HIF during AKI-to-CKD progression. This project intends to work on the novel basis of in-depth research to investigate the role and mechanism of TNFSF14 / HIF pathway during AKI-to-CKD. This study may provide new research ideas and intervention strategies for the prevention and treatment of AKI-to-CKD progress.

肾脏缺血缺氧和炎症反应是急性肾损伤（AKI）进展至慢性肾脏疾病（CKD）的重要机制。肾间质管周毛细血管网毁损在疾病进展过程中发挥重要作用，但其作用机制尚不明确。本课题组前期研究发现，肿瘤坏死因子超家族14（TNFSF14）可以引起微血管内皮细胞炎症反应，通过转录因子NF-κB途径刺激缺氧诱导基因（HIF）的转录，诱导和调控一系列血管活性因子的表达，编码多个血管活性蛋白，从而引起肾脏损伤和疾病进展。由此我们提出设想：TNFSF14可能通过对HIF的调控，进而对AKI-to-CKD 进展中的肾间质管周毛细血管内皮细胞损伤发挥重要作用。本项目拟在以上创新性工作基础上深入研究，探讨TNFSF14/HIF通路在AKI-to-CKD发生发展中的作用及机制。本研究可能为AKI 进展的防治提供新的研究思路和干预策略。

急性肾损伤（acute kidney injury，AKI）的发病率和死亡率逐年增高，AKI已成为全球公共卫生领域面临的重要问题。AKI-to-CKD的机制目前仍不十分清楚。因此，研究AKI-to-CKD过程中的相关标志物和关键致病因子，明确其发病机制，寻找潜在治疗靶点，防止和延缓肾功能进展迫在眉睫，具有广泛的社会效益和经济效益。本课题组在前期研究中发现，血管活性物质AngII能够刺激肾组织血管内皮细胞HIF-1α的基因表达，继而诱导和调控一系列血管活性因子表达，编码多个血管活性蛋白。AngII通过转录因子NF-κB途径刺激HIF-1α基因的转录，HIF-1α和NF-κB通过一个正反馈信号环路来发挥功能，维持肾组织血管内皮细胞中HIF-1α和NF-κB的持续高表达，引起肾脏缺血缺氧和炎症反应，从而导致肾脏损伤和促进肾脏疾病的进展。本研究在此基础上，构建小鼠AKI-to-CKD肾脏损伤疾病模型，制备中和抗体分别抑制TNFSF14两个受体的表达，采用Western Blot、Real-time PCR、ELISA、免疫组化等分子生物学方法，证实抑制TNFSF14/HIF通路，能够改善肾间质管周毛细血管内皮细胞在缺氧状态下的病理表现，减轻小鼠肾脏纤维化和炎症反应，进而阻断AKI-to-CKD进展。本研究从TNFSF14/HIF通路这一新角度，解析AKI-to-CKD发生发展中肾间质管周毛细血管内皮细胞病变进展的分子机制，首次提出并探讨TNFSF14/HIF通路在AKI-to-CKD发生发展中的作用及机制，为AKI-to-CKD进展的防治提供新的研究思路和干预策略。