Study of renal diseases caused by podocyte injury

足细胞损伤所致肾脏疾病的研究

• 批准号: 15209030
• 负责人: MATSUSAKA Taiji
• 金额: $ 31.53万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15209030/
• 关键词: podocyte; glomerular sclerosis; transgenic mice; HIV-1 associated nephropathy; angiotensin; chronic renal failure; actinin; 糸球体上皮細胞; アンジオテンシン; 糖尿病腎症

To investigate causal relationship between podocyte injury and glomerular sclerosis, a hallmark of chronic renal failure, we developed a transgenic mouse line (NEP25) in which podocyte-selective injury can be induced by a single injection of immunotoxin (LMB2). After LMB2 injection, NEP25 mice manifested injury of podocytes and other glomerular cells and rapidly developed glomerular sclerosis. Labeling of the podocyte-lineage utilizing the Cre-loxP system revealed that following downregulation of podocyte markers, podocytes were progressively lost, without transforming into other types of cell. Studies using chimeric mice revealed that injury initiated in a portion of podocytes was spread to other podocytes, thus forming a vicious cycle of self-perpetuating injury.Using other transgenic mouse lines that we developed, we demonstrated that in the presence of FVB/N genetic background, HIV-1 genes, vpr and nef, synergistically damage podocytes, leading to collapsing FSGS similar to HIV-1 associated nephropathy of humans.In both NEP25 and HIV-1 models, damage of podocytes was prevented remarkably by ureteral obstruction, indicating that continued glomerular filtration is a prerequisite for progressive injury of podocytes, and subsequent development of glomerular sclerosis.We also studied the role of mutant α-Actinin-4, which causes autosomal dominant focal segmental glomerular sclerosis (FSGS) in humans. Transgenic mice expressing mutant α-Actinin-4 in podocytes developed slowly progressive FSGS. By crossing α-Actinin-4 with NEP25 mice, we demonstrated that mutant α-Actinin-4 attenuated glomerular damage induced by LMB2.Thus, we demonstrated that in the presence of glomerular filtration, podocyte damage induced by various factors is automatically spread to other podocytes and types of cell within the glomerulus, which leads to glomerular sclerosis.

为了研究足细胞损伤与肾小球硬化（慢性肾衰竭的标志）之间的因果关系，我们开发了一种转基因小鼠系（NEP25），其中单次注射免疫毒素（LMB2）可诱导足细胞选择性损伤。注射LMB2后，NEP25小鼠出现足细胞等肾小球细胞损伤，迅速发展为肾小球硬化。利用Cre-loxP系统对足细胞谱系进行标记显示，在足细胞标记下调后，足细胞逐渐丢失，而不会转化为其他类型的细胞。嵌合小鼠的研究表明，一部分足细胞的损伤会扩散到其他足细胞，从而形成自我延续损伤的恶性循环。利用我们开发的其他转基因小鼠系，我们证明了在FVB/N遗传背景下，HIV-1基因vpr和nef会协同损害足细胞，导致FSGS塌陷，类似于人类HIV-1相关肾病。在NEP25和HIV-1模型中，输尿管梗阻明显阻止足细胞损伤，这表明肾小球滤过的持续存在是足细胞进行性损伤和肾小球硬化的先决条件。我们还研究了突变体α- actiin -4在人类常染色体显性局灶节段性肾小球硬化（FSGS）中的作用。在足细胞中表达突变α- actiin -4的转基因小鼠发生缓慢进行性FSGS。通过α- actiin -4与NEP25小鼠杂交，我们发现α- actiin -4突变体可以减轻LMB2引起的肾小球损伤。因此，我们证明，在肾小球滤过存在的情况下，由各种因素引起的足细胞损伤会自动扩散到肾小球内的其他足细胞和细胞类型，从而导致肾小球硬化。

项目成果

A role of BMP in the development of glomerular sclerosis.

BMP 在肾小球硬化发展中的作用。

• 发表时间: 2005
• 期刊: Nephrology (Carlton). 10 Supple6
• 作者: Ueda H;Miyazaki Y;Yokoo T;Utsunomiya Y;Kawamura T;Matsusaka T;Ichikawa I;Hosoya T.
• 通讯作者: Hosoya T.

Podocyte injury and glomerular sclerosis.

足细胞损伤和肾小球硬化。

• 发表时间: 2004
• 期刊: Nippon Rinsho. 62(20)
• 作者: Kato J;Kohyama T;Okazaki H;Desaki M;Rennard SI;Takizawa H;Nagase T.;Matsusaka T.
• 通讯作者: Matsusaka T.

Podocyte biology, insights from knock-out and transgenic mouse studies

足细胞生物学，基因敲除和转基因小鼠研究的见解

• 发表时间: 2003
• 期刊: Jin To Toseki. 55(5)
• 作者: Takai D;Nagase T;Shimizu T;Matsusaka T.
• 通讯作者: Matsusaka T.

J Zhong, A Fogo, I Ichikawa, T Matsusaka: "Role of Angiotensin II the Development of Focal Segmental Glomerulosclerosis (FSGS) in Human Immunodeficiency Virus (HIV)-1 Associated Nephropathy (HIVAN)."J Am Soc Nephrol (abstract). 14. 153A (2003)

J Chung、A Fogo、I Ichikawa、T Matsusaka：“血管紧张素 II 在人类免疫缺陷病毒 (HIV)-1 相关肾病 (HIVAN) 中局灶节段性肾小球硬化 (FSGS) 发展中的作用。”J Am Soc Nephrol（摘要）。

J Zhong, Y Zuo, J Ma, A Fogo, I Ichikawa, T Matsusaka: "Expression of HIV-1 Genes in Podocytes Alone Can Lead to Glomerulosclerosis."J Am Soc Nephrol (abstract). 14. 153A (2003)

J Chung、Y Zuo、J Ma、A Fogo、I Ichikawa、T Matsusaka：“足细胞中 HIV-1 基因的单独表达可导致肾小球硬化。”J Am Soc Nephrol（摘要）。