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)对140名蛋白尿患者进行尿液MAC排泄研究，并随访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)对人近端肾小管上皮细胞分离的刷状缘囊泡(BBVs)进行SDS-PAGE和转膜分析。 BBV 激活补体，并进一步分析了结合 C3b 的部分。结果表明，补体被 BBV 激活，并且存在结合 C3b 的片段。需要进一步分析BBVs中补体激活物质的特征。(3)进行性肾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。通过体内基因转移测试了阻止巨噬细胞浸润的策略。这种新方法的有效性在蛋白质重叠肾病大鼠模型中得到了证实。(4)分析了近端肾小管细胞中存在的靶分子，包括中期因子(MK)、Toll样受体和小窝蛋白。所有这些分子都被证明是体内和体外控制进行性肾损伤进展的靶标。(5)特别是，MK，一种新型肝素结合生长因子，在肾损伤期间其表达增加，并且MK 敲除小鼠的肾小管间质损伤程度显着减轻。此外，反义-ODN在近曲小管中抑制MK表达可显着减少体内肾损伤。(6)本研究项目获得的所有上述观察结果表明，多种机制/分子参与了肾损伤的进展，而临床应用则必须克服有效性、特异性、经济性、耐久性等障碍。

项目成果

蛋白尿による腎障害

蛋白尿导致肾脏损伤

• 发表时间: 2004
• 期刊: 内科 94
• 作者: Murase;N.;J.C.Rothwell;R.;Kaji;R.et al.;松尾清一
• 通讯作者: 松尾清一

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

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。

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》。