Glomerular filtrate affects the dynamics of podocyte detachment in a model of diffuse toxic podocytopathy
Glomerular filtrate affects the dynamics of podocyte detachment in a model of diffuse toxic podocytopathy
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DOI：
10.1016/j.kint.2020.12.034
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发表时间：
2021-04-20
影响因子：
19.6
通讯作者：
Nagata, Michio
中科院分区：
文献类型：
--
作者：
Saga, Nobuyuki;Sakamoto, Kazuo;Nagata, Michio
足细胞损伤和随后的脱离是进行性肾小球硬化的标志。除了细胞损伤外，作用于受损足细胞的未知机械力也可能促进脱离。为了确定这些机械力的性质，我们研究了足细胞脱离的动力学，通过透射电子显微镜在NEP 25中使用连续的超微结构几何分析，NEP 25是由抗Tac（Fv）-PE 38（LMB 2）诱导的足细胞病的小鼠模型，该融合蛋白附着于假单胞菌外毒素A，靶向足细胞上的CD 25。注射LMB 2后，足突消失发生在第三天，但脱离开始于第八天，并延长至第十天，到达尿极集群。足细胞脱离与足突消失有关，足突消失覆盖肾小球基底膜尺子的60%以上。然而，约25%的肾小球弥漫性（超过80%）足突消失显示无脱离。通过单侧输尿管梗阻阻断肾小球滤过导致弥漫性足突消失，但没有假性囊肿或脱离，而单侧肾切除术增加假性囊肿和加速脱离，表明肾小球滤过液通过假性囊肿形成驱动足细胞脱离作为先导。此外，在髓质肾小球中观察到更多的脱离比浅表肾小球。因此，肾小球滤液驱动足细胞病模型中足细胞脱离的动力学。因此，足突消失可能是一个先决条件，允许滤液产生局部机械力，扩大足细胞下空间形成假性囊肿，促进足细胞脱离和随后的节段性硬化。
Podocyte injury and subsequent detachment are hallmarks of progressive glomerulosclerosis. In addition to cell injury, unknown mechanical forces on the injured podocyte may promote detachment. To identify the nature of these mechanical forces, we studied the dynamics of podocyte detachment using sequential ultrastructural geometry analysis by transmission electron microscopy in NEP25, a mouse model of podocytopathy induced by anti-Tac(Fv)-PE38 (LMB2), a fusion protein attached to Pseudomonas exotoxin A, targeting CD25 on podocytes. After LMB2 injection, foot process effacement occurred on day three but detachment commenced on day eight and extended to day ten, reaching toward the urinary pole in clusters. Podocyte detachment was associated with foot process effacement covering over 60% of the glomerular basement membrane length. However, approximately 25% of glomeruli with diffuse (over 80%) foot process effacement showed no detachment. Blocking glomerular filtration via unilateral ureteral obstruction resulted in diffuse foot process effacement but no pseudocysts or detachment, whereas uninephrectomy increased pseudocysts and accelerated detachment, indicating that glomerular filtrate drives podocyte detachment via pseudocyst formation as a forerunner. Additionally, more detachment was observed in juxtamedullary glomeruli than in superficial glomeruli. Thus, glomerular filtrate drives the dynamics of podocyte detachment in this model of podocytopathy. Hence, foot process effacement may be a prerequisite allowing filtrate to generate local mechanical forces that expand the subpodocyte space forming pseudocysts, promote podocyte detachment and subsequent segmental sclerosis.