Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China.
Mol Ther. 2023 Nov 1;31(11):3337-3354. doi: 10.1016/j.ymthe.2023.09.003. Epub 2023 Sep 9.
Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction, which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin (ADR) to mimic human FSGS. In vivo, global AEP knockout mice manifested increased injury-susceptibility of podocytes in ADR-induced nephropathy (ADRN). Podocyte-specific AEP knockout mice exhibited much more severe glomerular lesions and podocyte injury after ADR injection. In contrast, podocyte-specific augmentation of AEP in mice protected against ADRN. In vitro, knockdown and overexpression of AEP in human podocytes revealed the cytoprotection of AEP as a cytoskeleton regulator. Furthermore, transgelin, an actin-binding protein regulating actin dynamics, was cleaved by AEP, and, as a result, removed its actin-binding regulatory domain. The truncated transgelin regulated podocyte actin dynamics and repressed podocyte hypermotility, compared to the native full-length transgelin. Together, our data reveal a link between lysosomal protease AEP and podocyte cytoskeletal homeostasis, which suggests a potential therapeutic role for AEP in proteinuria disease.
局灶节段性肾小球硬化症（FSGS）是导致全球终末期肾病的最常见肾小球疾病。FSGS 的发病机制主要是足细胞功能障碍，这是由多种损伤诱导的。然而，足细胞损伤和修复的机制在很大程度上仍未被探索。天冬酰胺内肽酶（AEP）是一种溶酶体蛋白酶，通过残基特异性切割或降解来调节底物。我们在阿霉素（ADR）诱导的原发性蛋白尿模型中发现 AEP 表达增加，该模型模拟人类 FSGS。在体内，全局 AEP 敲除小鼠在 ADR 诱导的肾病（ADRN）中表现出对足细胞损伤的敏感性增加。足细胞特异性 AEP 敲除小鼠在 ADR 注射后表现出更严重的肾小球病变和足细胞损伤。相比之下，在小鼠中特异性增强 AEP 表达可预防 ADRN。在体外，人足细胞中 AEP 的敲低和过表达揭示了 AEP 作为细胞骨架调节剂的细胞保护作用。此外，天冬酰胺内肽酶可切割肌动蛋白结合蛋白转胶蛋白，从而去除其肌动蛋白结合调节结构域。与天然全长转胶蛋白相比，截断的转胶蛋白调节足细胞肌动蛋白动力学并抑制足细胞过度运动。总之，我们的数据揭示了溶酶体蛋白酶 AEP 与足细胞细胞骨架动态平衡之间的联系，这表明 AEP 在蛋白尿疾病中具有潜在的治疗作用。
