Research on The Role of Proximal Tubular Cells in The Development of Tubulointerstitinal Injury.

本项目旨在研究近端小管细胞（ptc）在促进小管间质炎症和纤维化中的作用。高浓度葡萄糖作用下，ptc产生的结缔组织生长因子（CTGF）增加。这种现象部分由TGF-β介导，但TGF-β独立通路也起作用，ptc被细菌脂多糖（LPS）激活，产生MCP-1和RANTES等趋化因子。这是由toll样受体4 （TLR4）介导的。MCP-1和RANTES产生的细胞内信号通路不同，即JNK或NF-κ B用于MCP-1，而p38用于RANTES。在体内实验中，通过肾静脉逆行注射将突变的MCP-1基因转入大鼠肾间质细胞，成功地抑制了蛋白超载肾病引起的肾小管间质损伤。从这些数据来看，ptc或间质细胞可能是治疗的目标。

This project was performed to investigate the roles of proximal tubular cells (PTCs) in the promotion of tubulointerstitial inflammation and fibrosis. PTCs produced increased amount of connective tissue growth factor (CTGF) under high concentration of glucose. This phenomenon was partially mediated by TGF-β, but TGF-β independent pathway was also working, PTCs were activated by the bacterial lipopolysaccharide (LPS) resulting in production of chemokines such as MCP-1 and RANTES. This is mediated by toll-like receptor 4 (TLR4). Intracellular signaling pathways of MCP-1 and RANTES production was different, i.e., JNK or NF-κ B for MCP-1 while p38 for RANTES. In the in vivo experiment, gene transfer of mutated MCP-1 gene into rat kidney interstitial cells by retrograde injection via renal vein successfully inhibited tubulointerstitial injury induced by the protein overload nephropathy. From these data, it is suggested that PTCs or interstitial cells can be the target of therapy.