Basic research for the development of new therapeutic measures against progressive tubuloinetsrtitial injury.

开发针对进行性肾小管损伤的新治疗措施的基础研究。

• 批准号: 15390269
• 负责人: MATSUO Seiichi
• 金额: $ 9.54万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390269/
• 关键词: progressive renal injury; Tubulointerstitial Injury; Proteinuria; Complement; Novel Therapy; Renal Protection; Cellular Infiltration; Renal Fibrosis; 近位尿細管細胞; 尿再管間質障害; brush border vesicle; ケモカイン; C3; MCP-1; マクロファージ

(1)Urinary MAC excretion was studied in 140 patients with proteinuria and followed up for 40 months. Multi-factorial analysis revealed that the increased urinary MAC excretion was an independent risk factor for progression of renal injury.(2)Brush border vesicles(BBVs) isolated from human proximal tubular epithelial cells were analyzed by SDS-PAGE and transfer membrane. BBVs activated complement and the fraction binding C3b was further analyzed. It was shown that complement was activated by BBVs and there were fragments to bind C3b. The further analysis is necessary to characterize complement activating substances in BBVs.(3)One of the main mechanisms of progressive tubulointerstitial injury is the infiltration of macrophages/monocytes. The strategy to iniibit macrophage infiltration was tested by using in vivo gene transfer. The effectiveness of this newly developed method was proven in a rat model of protein overlaod nephropathy.(4)The target molecules existing in the proximal tubular cells including midkine(MK), toll like receptors, and caveolin were analyzed. All of these molecules were proven to be a target to manipulate progression og the progressive renal injury in vivo and in vitro.(5)In particularly, MK, a novel heparin-binding growth factor, is increased in its expression during renal injury, and the extent of tubulointerstitial injury was significantly lessened in MK knock out mice. Furthermore, inhibition of MK expression by antisense-ODN in the proximal tubules significantly reduced renal injury in vivo.(6)All of the above observation obtained by the present research project revealed that several mechanismas/molecules were involved in the progression of renal injury, and for the clinical use, we must overcome the hurdles concerning efficacy, specificity, economy, and durability.

(1)观察140例蛋白尿患者尿MAC排泄情况，随访40个月。多因素分析显示尿MAC排泄增加是肾损伤进展的独立危险因素。(2)利用SDS-PAGE和转移膜对人近端小管上皮细胞的刷状边界囊泡（bbv）进行分析。进一步分析bbv活化补体和结合C3b的部分。结果表明，补体可被bbv激活，并且存在与C3b结合的片段。进一步的分析是必要的，以表征补体激活物质在bbv。(3)进行性小管间质损伤的主要机制之一是巨噬细胞/单核细胞的浸润。采用体内基因转移法对抑制巨噬细胞浸润的策略进行了验证。这种新方法的有效性在蛋白质超载肾病大鼠模型中得到了证实。(4)分析了近端小管细胞中存在的靶分子，包括midkine（MK）、toll样受体和caveolin。所有这些分子都被证明是体内和体外操纵进行性肾损伤进展的靶标。(5)特别是，新型肝素结合生长因子MK在肾损伤过程中表达增加，MK敲除小鼠肾小管间质损伤程度明显减轻。此外，反义odn在近端小管中抑制MK表达可显著减少体内肾损伤。(6)本研究项目的上述观察结果表明，多种机制/分子参与了肾损伤的进展，对于临床应用，我们必须克服有效性、特异性、经济性和持久性的障碍。

项目成果

Proteinuria and tubulointerstitial injury : the causative factors for the progression of renal diseases.

蛋白尿和肾小管间质损伤：肾脏疾病进展的致病因素。

• 发表时间: 2003
• 期刊: Contributions to Nephrology 139
• 作者: Matsuo S

A srine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL12 production and helper T cell differentiation.

丝氨酸/苏氨酸激酶 Cot/Tpl2 可调节细菌 DNA 诱导的 IL12 产生和辅助 T 细胞分化。

• 发表时间: 2004
• 期刊: Journal of Clinical Investigation 114
• 作者: Sugimoto K;Ohata M;Miyoshi J;H.I;Tsuboi N;Masuda A;Yoshikai Y;Takamoto M;Sugane K;Matsuo S;Shimada Y;Matsuguchi T
• 通讯作者: Matsuguchi T

Liu M: "The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids"Clinical and Experimental Nephrology. 7. 187-191 (2003)

刘明：“关马兜铃对大鼠的肾毒性归因于其中的马兜铃酸”，《临床与实验肾脏病学》。

Fukuda N: "Identification of a novel GDNF-inducible required for renal branching morphogenesis"Journal of Biological Chemistry. 278. 50386-50392 (2003)

Fukuda N：“肾分支形态发生所需的新型 GDNF 诱导物的鉴定”生物化学杂志。

Shimizu H: "Anti-monocyte chemoattravtant protein-1 gene therapy attenuates renal injury induced by protein overload proteinuria"Journal of The American Society of Nephrology. 14. 1496-1505 (2003)

Shimizu H：“抗单核细胞趋化蛋白-1 基因治疗可减轻蛋白质超载蛋白尿引起的肾损伤”美国肾脏病学会杂志。