The role of cyclin dependent kinase-5 in podocytes differentiation and maintenance of podocytes shape and its function.

细胞周期蛋白依赖性激酶 5 在足细胞分化和维持足细胞形状及其功能中的作用。

• 批准号: 15590843
• 负责人: HIROMURA Keiju
• 金额: $ 1.6万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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-15590843/
• 关键词: podocyte; cyclin dependent kinase; CDK5; cell cycle regulatory protein; differentiation; glomerulonephritis; HIV associated nephropathy

We investigated the role of cyclin dependent kinase 5 (CDK5) in podocytes differentiation and the maintenance of podocytes shape and its function, using mice model of HIV nephropathy. The mice (rtTA-Vpr) were generated to express one of HIV accessory protein, Vpr, predominantly in podocytes, using podocin promoter and tet-on system. By the combination of heminephrectomy and administration of doxycycline, mice developed collapsing or cellular type focal segmental sclerosis with massive proteinuria, resembling human HIV-associated nephropathy. During the development of glomerulosclerosis, dedifferentiation of podocytes was observed. Using this model, we examined the expression of CDK5. The expression of CDK5 decreased and disappeared during the dedifferentiation of podocytes. The markers of podocytes differentiation, such as WT-1 and synaptopodin, similarly decreased and disappeared. We also examined cyclin D3, which binds to CDK5, but not activates CDK5. The expression of cyclin D3 also decreased and disappeared. On the contrary, PCNA, the marker of cell proliferation was detected in dedifferentiated podocytes, demonstrating that these cells were in cell cycle for proliferation. These changes were observed in the podocytes those did not changed morphologically by a light microscope, although at the time when massive proteinuria was already detected.In conclusion, CDK5 and its related protein were shown to decrease and disappear during the podocytes dedifferentiation in mice model of HIV nephropathy, in which massive proteinuria and glomeruloselerosis were observed. These results suggest that CDK5 and its related protein play a role in differentiated podocytes to maintain its function. Loss of these molecules may lead to proteinuria and glomerulosclerosis.

本研究利用HIV肾病小鼠模型，探讨细胞周期蛋白依赖性激酶5（CDK 5）在足细胞分化、维持足细胞形态和功能中的作用。利用podocin启动子和tet-on系统，产生主要在足细胞中表达HIV辅助蛋白Vpr之一的小鼠（rtTA-Vpr）。通过半肾切除术和多西环素给药的组合，小鼠发展为塌陷或细胞型局灶性节段性硬化症，伴有大量蛋白尿，类似于人类HIV相关肾病。在肾小球硬化的发展过程中，观察到足细胞的去分化。使用该模型，我们检测了CDK 5的表达。在足细胞脱分化过程中，CDK 5的表达逐渐减少甚至消失。足细胞分化的标志物，如WT-1和synaptopodin，同样减少和消失。我们还研究了细胞周期蛋白D3，它结合CDK 5，但不激活CDK 5。细胞周期蛋白D3的表达也减少或消失。相反，在去分化足细胞中检测到细胞增殖标记物PCNA，表明这些细胞处于增殖的细胞周期中。在光镜下观察到的足细胞形态学上没有变化，但此时已经检测到大量蛋白尿。总之，在HIV肾病小鼠模型中，在足细胞去分化过程中，CDK 5及其相关蛋白减少并消失，其中观察到大量蛋白尿和肾小球硬化。这些结果表明，CDK 5及其相关蛋白在分化的足细胞中发挥作用，以维持其功能。这些分子的丢失可能导致蛋白尿和肾小球硬化。

项目成果

Heminephrectomy acclerates the progression of glomerulosclerosis in the conditional transgenic mice expressing HIV Vpr gene in podocytes : implication of intraglomerular pressure for the progression of collapsing FSGS. (3rd World Congress of Nephrology, A

半肾切除术加速足细胞表达 HIV Vpr 基因的条件转基因小鼠的肾小球硬化进展：肾小球内压力对塌陷 FSGS 进展的影响。

• 发表时间: 2005
• 期刊: Nephrology 10 suppl.
• 作者: Noriyuki Hiramatsu;Tetsuya Shigehara;Takashi Kuroiwa;Hidekazu Ikeuchi;Keiju Hironuma;Yoshihisa Nojima;Jeffrey B. Kopp
• 通讯作者: Jeffrey B. Kopp

Analysis of cell cycle protein during podocytes injuries using accelerated mice model of HIV nephropathy.

使用 HIV 肾病加速小鼠模型分析足细胞损伤期间的细胞周期蛋白。

• 发表时间: 2005
• 期刊: Journal of Japanese Society of Nephrology Vol.47(Abstract)
• 作者: Hiroshi Ideura;Keiju Hiromura;Noriyuki Hirmatsu;Tetsuya Shigehara;Shin Ymashita;Takashi Kuroiwa;Yoriaki Kaneko;Kazue Ueki;Yoshihisa Nojima;Jeffrey B.Kopp
• 通讯作者: Jeffrey B.Kopp

加速型HIV腎症モデルマウスを用いた糸球体上皮細胞障害における細胞周期制御蛋白の検討(第48回日本腎臓学会学術総会 会議録)

使用加速HIV肾病模型小鼠检查肾小球上皮细胞损伤中的细胞周期控制蛋白（第48届日本肾病学会年会论文集）

• 发表时间: 2005
• 期刊: 日本腎臓学会誌 47
• 作者: 出浦 洋;廣村桂樹;平松範行;重原哲也;山下 眞;黒岩 卓;金子和光;植木嘉衛;野島美久;Jeffrey Kopp
• 通讯作者: Jeffrey Kopp

Development of accelerated mice model of HIV nephropathy by prodocytes specific expression of vpr and Heminephrectomy.

通过 vpr 的前体细胞特异性表达和半肾切除术开发 HIV 肾病加速小鼠模型。

• 发表时间: 2005
• 期刊: Journal of Japanese Society of Nephrology Vol.47(Abstract)
• 作者: Noriyuki Hiramatsu;Tetsuya Shigehara;Takashi Kuroiwa;Hiroshi Ideura;Hidekazu Ikeuchi;Keiju Hiromura;Kazue Ueki;Yoshihisa Nojima;Jeffrey B.Kopp
• 通讯作者: Jeffrey B.Kopp

Heminephrectomy accelerated the progresion of glomerulosclerosis in the conditional transgenic mice expression g HIV Vpr gene in podocytes : implication of intraglomerular pressure for the prograssion of collapsing FSGS.

半肾切除术加速了足细胞中表达 g HIV Vpr 基因的条件转基因小鼠的肾小球硬化进展：肾小球内压力对塌陷 FSGS 进展的影响。

• 发表时间: 2005
• 期刊: Nephrology Vol.10(Abstract)
• 作者: Noriyuki Hiramatsu;Tetsuya Shigehara;Takashi Kuroiwa;Hidekaza Ikeuchi;Keiju Hiromura;Yoshihisa Nojima;Jeffrey B.Kopp
• 通讯作者: Jeffrey B.Kopp