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

近端肾小管细胞在肾小管间质损伤发展中作用的研究。

• 批准号: 13671110
• 负责人: MATSUO Seiichi
• 金额: $ 2.11万
• 依托单位: NAGOYA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671110/
• 关键词: tubulointerstitial injury; progressive renal deisease; renal fibrosis; diabetic nephropathy; chemokine; toll-like receptors (TLRs); gene therapy; connective tissue growth factor (CTGF); 腎繊維化; toll-like receptors(TLRs); connective tissue growth f

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.

该项目旨在研究近端肾小管细胞 (PTC) 在促进肾小管间质炎症和纤维化中的作用，在高浓度葡萄糖下，PTC 会产生大量结缔组织生长因子 (CTGF)，这种现象部分是由 TGF-介导的。 β，但 TGF-β 独立途径也在起作用，PTC 被细菌脂多糖 (LPS) 激活，导致产生趋化因子，如 MCP-1 和RANTES。这是由 Toll 样受体 4 (TLR4) 介导的。在体内实验中，MCP-1 和 RANTES 产生的细胞内信号通路不同，即 MCP-1 为 JNK 或 NF-κ B，而 RANTES 为 p38。 ，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，成功抑制了蛋白质超载引起的肾小管间质损伤从这些数据来看，PTC 或间质细胞可以作为治疗的目标。

项目成果

Naotake Tsuboi: "Roles of Toll-Like Receptors in C-C Chemokine Production by Renal Tubular Epithelial Cells"Journal of Immunology. 169. 2026-2033 (2002)

Naotake Tsuboi：“Toll 样受体在肾小管上皮细胞产生 C-C 趋化因子中的作用”免疫学杂志。

Ikeguchi, Hiroshi: "Effects of soluble human thrombomodulin in expreimental glomerulonephritis"Kidney Int. 61. 490-501 (2001)

池口宏：“可溶性人血栓调节蛋白对实验性肾小球肾炎的影响”Kidney Int。

Kazuhiro Ishiguro: "Syndecan-4 deficiency increases susceptibility to κ-carrageenan-induced renal damage"Laboratory Investigation. 81. 509-516 (2001)

Kazuhiro Ishiguro：“Syndecan-4 缺乏症降低了对 κ-角叉菜胶诱导的肾损伤的敏感性”实验室研究 81. 509-516 (2001)。

Tomohiko Naruse: "P-selectin -dependent macrophage migration into the tubulointerstitium in unilateral ureteral obstruction"Kidney International. 62. 94-105 (2002)

Tomohiko Naruse：“单侧输尿管梗阻时 P-选择素依赖性巨噬细胞迁移至肾小管间质”国际肾脏病杂志。

Tuboi N, Yoshikai Y, Matsuo S, Kikuchi T, Iwai K, Nagai N, Takeuchi O, Akira S, Matsuguchi T: "Roles of Toll-Like Receptors in C-C Chemokine Production by Renal Tubular Epithelial Cells"Journal of Immunology. 169. 2026-2033 (2002)

Tuboi N、Yoshikai Y、Matsuo S、Kikuchi T、Iwai K、Nagai N、Takeuchi O、Akira S、Matsuguchi T：“Toll 样受体在肾小管上皮细胞产生 C-C 趋化因子中的作用”免疫学杂志。