Regeneration of sclerosed glomeruli : Mechanism of dedifferentiation and phenotypic changes in podocytes and induce redifferentiation.

硬化肾小球的再生：足细胞去分化和表型变化并诱导再分化的机制。

• 批准号: 17590818
• 负责人: NAGATA Michio
• 金额: $ 2.18万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590818/
• 关键词: kidney; glomerulosclerosis; podocyte; differentiation; phenotype; glomerulonephritis; nestin; regeneration; トランスジェニックマウス; ROSAマウス; nephrin-Cre; 抗基底膜抗体腎炎; 上皮脱分化

To monitor podocytes derived cells in the pathologic process of glomerular disease, we generate Nephrin-Cre/Rosa26 mice and then we crossed them with p21 deficient mice and induced anti-glomerular antibody glomerulonephritis. The kidney showed marked proteinuria coupled with glomerular epithelial hyperplasia. To analyze the origin and phenotype of these cells, immunohistochemistry for several podocytes markers and incorporation of BrdU was analyzed. Hypercellular lesions were virtually both LacZ and WT1 negative. In addition, we did not find out for LacZ+/WT1-cells or LacZ+/synaptopodin-cells. Thus podocytes dedifferentiation is not occurring in this setting of experimental glomerulonephritis.We are now investigating the plasticity of podocytes focusing on the function of nestin intermediate filament, neurogenic progenitor marker, we found nestin is predominantly expressed in the differentiated podocytes and cytoplasmic distribution of nestin is different from that of actin.siRNA of nestin for immortalized podocytes cell line reveals suppression of process formation suggesting nestin function for podocytes plasticity.

为了监测足细胞来源的细胞在肾小球疾病的病理过程中的作用，我们建立了Nephin-Cre/rosa26小鼠，并将它们与p21基因缺陷的小鼠杂交，诱导了抗肾小球抗体肾炎。肾脏有明显的蛋白尿，伴有肾小球上皮细胞增生。为了分析这些细胞的来源和表型，对几种足细胞标志物和BrdU的掺入进行了免疫组织化学分析。实质上，LacZ和WT1均为阴性的高细胞病变。此外，我们没有发现LacZ+/WT1-细胞或LacZ+/synaptopodin-细胞。因此，在这种实验性肾小球肾炎的情况下，足细胞不会发生去分化。我们目前正在研究足细胞的可塑性，重点是Nestin中间丝的功能，我们发现Nestin主要在分化的足细胞中表达，并且Nestin的细胞质分布不同于Actin。永生化的足细胞系的Nestin的siRNA显示突起形成的抑制，提示Nestin在足细胞可塑性中的作用。