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IF 10.3 1区医学 Q1 UROLOGY & NEPHROLOGY

Journal of The American Society of Nephrology Pub Date : 2025-02-28 DOI:10.1681/ASN.0000000614

Naoyuki Shimada, Jun Matsuda, Kana Asano-Matsuda, Maho Tokuchi, Lamine Aoudjit, Agnieszka Masztalerz, Serge Lemay, Tomoko Takano, Yoshitaka Isaka

引用次数: 0

摘要

背景：荚膜细胞具有复杂的结构，其特点是有许多基于肌动蛋白的突起，称为足突。Rho家族的小GTP酶，包括与Ras相关的C3肉毒毒素底物1（Rac1），在细胞形态和粘附所需的肌动蛋白细胞骨架重塑中发挥重要作用。我们以前曾发现，荚膜细胞中的 Rac1 激活会导致足突脱落和蛋白尿，但 Rac1 的上游和时空调控机制尚不清楚。最近，我们通过近距离依赖性生物素鉴定（BioID）和蛋白质组学方法，确定了病灶粘附蛋白 GIT ArfGAP2（GIT2）是人荚膜细胞中 Rac1 的相互作用因子之一：方法：产生全身性和荚膜特异性 GIT2 基因敲除小鼠，并对其肾脏表型进行评估。利用慢病毒转导技术建立了基因敲除和过表达 GIT2 的人类荚膜细胞，并对其进行了表征：结果：GIT2富集于肾小球，包括小鼠肾脏中的荚膜细胞。在最小变化疾病模型和盐敏感性高血压模型中，荚膜细胞中 Git2 的基因缺失会导致蛋白尿加重和足突消失，而药物抑制 Rac1 则可改善这种情况。在培养的荚膜细胞中，敲除 GIT2 会导致依赖 Rac1 的细胞扩散，并伴有明显的薄壁突起，加速局灶粘附的解体，缩短局灶粘附的寿命。在 GIT2 基因敲除的荚膜细胞中，病灶粘附蛋白 p130 Crk-associated substrate（Cas）的酪氨酸磷酸化显著增加，同时酪氨酸磷酸酶 PTP1B 在病灶粘附处的定位也受损。在 GIT2 敲除的荚膜细胞中观察到的这些表型被 GIT2 过表达所逆转：研究结果表明，GIT2 能促进 PTP1B 转位至病灶粘附处，使 p130Cas 去磷酸化，从而抑制局部 Rac1 的活性，防止荚膜细胞损伤和蛋白尿。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection.

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来源期刊

Journal of The American Society of Nephrology 医学-泌尿学与肾脏学

CiteScore

22.40

自引率

2.90%

发文量

492

审稿时长

3-8 weeks

期刊介绍： The Journal of the American Society of Nephrology (JASN) stands as the preeminent kidney journal globally, offering an exceptional synthesis of cutting-edge basic research, clinical epidemiology, meta-analysis, and relevant editorial content. Representing a comprehensive resource, JASN encompasses clinical research, editorials distilling key findings, perspectives, and timely reviews. Editorials are skillfully crafted to elucidate the essential insights of the parent article, while JASN actively encourages the submission of Letters to the Editor discussing recently published articles. The reviews featured in JASN are consistently erudite and comprehensive, providing thorough coverage of respective fields. Since its inception in July 1990, JASN has been a monthly publication. JASN publishes original research reports and editorial content across a spectrum of basic and clinical science relevant to the broad discipline of nephrology. Topics covered include renal cell biology, developmental biology of the kidney, genetics of kidney disease, cell and transport physiology, hemodynamics and vascular regulation, mechanisms of blood pressure regulation, renal immunology, kidney pathology, pathophysiology of kidney diseases, nephrolithiasis, clinical nephrology (including dialysis and transplantation), and hypertension. Furthermore, articles addressing healthcare policy and care delivery issues relevant to nephrology are warmly welcomed.