尿酸活化NLRP3炎症小体介导足细胞损伤机制的研究

Hyperuricemia was a independent risk factor for chronic kidney disease (CKD). Glomerular epithelial cells, podocytes, are highly specialized cells that serve as a crucial component of the glomerular filtration barrier. It is becoming increasingly clear that podocyte injury leads to proteinuria and occurs in many glomerular diseases that finally progress to CKD.Elevated uric acid might have an direct effect on podocyte as an prooxidative factor. Our previous studies have demonstrated that uric induced podocyte injury and NLRP3 inflammasome activation as well. However, the underlying regulatory mechanisms of uric acid in podocyte injury remain far from clear. In a series of preliminary experiments we found that NLRP3 inflammasome activation could cause poodcyte injury. Therefore, we hypothesize that uric acid might trigger podocyte injury via NLRP3 inflammasome activation. To establish our main hypothesis, the molecular mechanism of uric acid on NLRP3 inflammasome activation and podocyte injury will be tested via overexpression of NLRP3, RNAi suppression of NLRP3 and podocyte specific knock out NLRP3 gene mouse. These studies are expected to open a new avenue in the understanding of uric acid induced podocyte injury, which may guide us in therapeutic strategies for CKD.

高尿酸血症能作为独立危险因素参与慢性肾脏病的进展。足细胞损伤是慢性肾脏病蛋白尿和肾小球硬化的重要病理基础，是多种损伤形式（如氧化应激）作用的靶细胞。足细胞胞体浸泡于原尿中，增高的尿酸作为促氧化应激因子可直接作用于足细胞。前期实验发现尿酸刺激可致足细胞损伤（nephrin及podocin表达下降），炎症小体活化（NLRP3表达增加，IL-18分泌增加），但对这些现象的机制至今不清。在上一个课题研究中发现，NLRP3炎症小体活化可导致足细胞损伤。由此推测，尿酸可通过活化NLRP3炎症小体，介导足细胞损伤。本课题将通过过表达，siRNA等技术，及课题组首次成功构建的足细胞特异性敲除NLRP3基因小鼠模型，来探讨尿酸对NLRP3炎症小体活化及足细胞损伤的影响及其分子机制。