Analysis of glomerulosclerotic mechanism by monoclonal antibody-induced progressive renal lesion model in rats

单克隆抗体诱导大鼠进行性肾损伤模型分析肾小球硬化机制

• 批准号: 08457286
• 负责人: SHIMIZU Fujio
• 金额: $ 4.74万
• 依托单位: Niigata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457286/
• 关键词: monoclonal antibody; glomerulosclerosis; proteinuria; adhesivemolecule; cytokine; extracellular matrix; macrophage; マクロファージ; ACE阻害剤

I rreversible sclerotic renal lesions were induced in rats by an intravenous injection of 500 ug of anti-Thy-1.1 monoclonal antibody (mAb) 1-22-3to unilaterally nephrectomized rats. This modelis characterized by the sustained marked proteinuria with typical sclerotic lesions in glomeruli as well as in tubulointerstitium. These lesions were inhibited by adhesive molecules suppressants, complement inhibitors, anti-fibrotic agents, ACE inhibitors and Chinese traditional medicines. We have compared the kinetics of various parametersofirreversible to those in reversiblemodels, both of which were induced by an intravenous injection of mAb 1-22-3. In irreversible models TRPM3-positive activated macrophage and alpha -smoothe muscle actin-positive cells were demonstrated to infiltrate to interstitium, even in relatively early phase, suggesting the important roles playd by these tubulointerstitiallesionsin leading to irreversiblescleroticlesions. Angiotensin receptorantagonist prevented progression to endo-stage renal failure by suppressing the expression of TGF-beta and type I,III collagens at mRNA and protein levels, indicating that these factors are also important for irreversible progression of renal lesions.

用抗Thy-1.1单克隆抗体（mAb）1-22- 3（500 μ g）静脉注射单侧肾切除大鼠，诱发不可逆性硬化性肾损害。该模型的特征是持续的显著蛋白尿，肾小球和肾小管有典型的硬化病变。粘附分子抑制剂、补体抑制剂、抗纤维化药物、ACE抑制剂和中药可抑制这些病变。我们比较了静脉注射mAb 1-22-3诱导的不可逆模型和可逆模型中各种参数的动力学。在不可逆性模型中，TRPM 3阳性的活化巨噬细胞和α-平滑肌肌动蛋白阳性细胞被证明浸润到肾小管，即使在相对早期的阶段，表明这些肾小管病变在导致不可逆性硬化病变中起重要作用。血管紧张素受体拮抗剂通过在mRNA和蛋白水平抑制TGF-β和I、III型胶原的表达来阻止进展为终末期肾衰竭，表明这些因素对于肾脏病变的不可逆进展也是重要的。

项目成果

Li P: "Suppressive effects of Sairei-to on monoclonal antibody 1-22-3-induced glomerulonephritis:Analysis of effective components" Pathol Int.47. 430-435 (1997)

李平：“Sairei-to对单克隆抗体1-22-3诱导的肾小球肾炎的抑制作用：有效成分分析”Pathol Int.47。

Li P: "Effect of Sairei-to on irreversible glomerular sclerotic lesions in rats" Nephrol(in press).

Li P：“Sairei-to 对大鼠不可逆肾小球硬化病变的影响”Nephrol（出版中）。

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Narisawa-Saito, M.、Yamanashi, Y.、Morioka, T.、Oite, T.、Shimizu, F.：“Thy-1 分子与大鼠系膜细胞中的蛋白酪氨酸激酶相关。”

Nakayama, M., Okuda, S., Tamaki, K., Shimizu, F., Kawachi, H., Ando, T., Yanagida, T., Fujishima M.: "Roles of TGF-beta and latent TGF-beta-binding protein in glomerulosclerosis induced by two consecutive injections of monoclonal Aantibody 1-22-3 in rats.

Nakayama, M.、Okuda, S.、Tamaki, K.、Shimizu, F.、Kawachi, H.、Ando, T.、Yanagida, T.、Fujishima M.：“TGF-β 和潜在 TGF-β 的作用

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