Smeets Bart, Te Loeke Nathalie A J M, Dijkman Henry B P M, Steenbergen Mark L M, Lensen Joost F M, Begieneman Mark P V, van Kuppevelt Toin H, Wetzels Jack F M, Steenbergen Eric J
Department of Pathology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
J Am Soc Nephrol. 2004 Apr;15(4):928-39. doi: 10.1097/01.asn.0000120559.09189.82.
Focal segmental glomerulosclerosis (FSGS) is a hallmark of progressive renal disease. Podocyte injury and loss have been proposed as the critical events that lead to FSGS. In the present study, the authors have examined the development of FSGS in Thy-1.1 transgenic (tg) mice, with emphasis on the podocyte and parietal epithelial cell (PEC). Thy-1.1 tg mice express the Thy-1.1 antigen on podocytes. Injection of anti-Thy-1.1 mAb induces an acute albuminuria and development of FSGS lesions that resemble human collapsing FSGS. The authors studied FSGS lesions at days 1, 3, 6, 7, 10, 14, and 21, in relation to changes in the expression of specific markers for normal podocytes (WT-1, synaptopodin, ASD33, and the Thy-1.1 antigen), for mouse PEC (CD10), for activated podocytes (desmin), for macrophages (CD68), and for proliferation (Ki-67). The composition of the extracellular matrix (ECM) that forms tuft adhesions or scars was studied using mAb against collagen IV alpha2 and alpha4 chains and antibodies directed against different heparan sulfate species. The first change observed was severe PEC injury at day 1, which increased in time, and resulted in denuded segments of Bowman's capsule at days 6 and 7. Podocytes showed foot process effacement and microvillous transformation. There was no evidence of podocyte loss or denudation of the GBM. Podocytes became hypertrophic at day 3, with decreased expression of ASD33 and synaptopodin and normal expression of WT-1 and Thy-1.1. Podocyte bridges were formed by attachment of hypertrophic podocytes to PEC and podocyte apposition against denuded segments of Bowman's capsule. At day 6, there was a marked proliferation of epithelial cells in Bowman's space. These proliferating cells were negative for desmin and all podocyte markers, but stained for CD10, and thus appeared to be PEC. The staining properties of the early adhesions were identical to that of Bowman's capsule, suggesting that the ECM in the adhesions was produced by PEC. In conclusion, the authors propose the following sequence of events leading to FSGS lesions in the Thy1.1 tg mice: (1) PEC damage and denudation of Bowman's capsule segments; (2) podocyte hypertrophy and bridging; and (3) PEC proliferation with ECM production.
局灶节段性肾小球硬化（FSGS）是进行性肾脏疾病的一个标志。足细胞损伤和丢失被认为是导致FSGS的关键事件。在本研究中，作者研究了Thy-1.1转基因（tg）小鼠中FSGS的发展，重点关注足细胞和壁层上皮细胞（PEC）。Thy-1.1 tg小鼠在足细胞上表达Thy-1.1抗原。注射抗Thy-1.1单克隆抗体可诱导急性蛋白尿和FSGS病变的发展，这些病变类似于人类塌陷性FSGS。作者在第1、3、6、7、10、14和21天研究了FSGS病变，以及正常足细胞（WT-1、突触素、ASD33和Thy-1.1抗原）、小鼠PEC（CD10）、活化足细胞（结蛋白）、巨噬细胞（CD68）和增殖（Ki-67）特异性标志物表达的变化。使用抗IV型胶原α2和α4链的单克隆抗体以及针对不同硫酸乙酰肝素种类的抗体研究了形成肾小球毛细血管袢粘连或瘢痕的细胞外基质（ECM）的组成。观察到的第一个变化是第1天出现严重的PEC损伤，且随时间增加，在第6和7天导致鲍曼囊节段裸露。足细胞显示足突消失和微绒毛转化。没有证据表明足细胞丢失或肾小球基底膜裸露。足细胞在第3天肥大，ASD33和突触素表达降低，WT-1和Thy-1.1表达正常。肥大的足细胞与PEC附着并与鲍曼囊裸露节段并列形成足细胞桥。在第6天，鲍曼间隙中的上皮细胞显著增殖。这些增殖细胞结蛋白和所有足细胞标志物呈阴性，但CD10染色阳性，因此似乎是PEC。早期粘连的染色特性与鲍曼囊相同，表明粘连中的ECM由PEC产生。总之，作者提出了Thy1.1 tg小鼠中导致FSGS病变的以下事件顺序：（1）PEC损伤和鲍曼囊节段裸露；（2）足细胞肥大和桥接；（3）PEC增殖并产生ECM。
