Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin
Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin
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DOI：
10.1016/j.ymthe.2023.09.003
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发表时间：
2023-11-01
影响因子：
12.4
通讯作者：
Zhang，Chun
中科院分区：
文献类型：
--
作者：
Qiu，Yang;Lei，Chuntao;Zhang，Chun
局灶节段性肾小球硬化症（FSGS）是全世界最常见的导致终末期肾病的肾小球疾病。 FSGS 发病机制的核心是足细胞功能障碍，这是由多种损伤引起的。然而，控制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。我们在模拟人 FSGS 的阿霉素 (ADR) 诱导的原发性蛋白尿模型中发现了 AEP 表达增加。在体内，整体 AEP 敲除小鼠在 ADR 诱导的肾病 (ADRN) 中表现出足细胞损伤易感性增加。足细胞特异性 AEP 敲除小鼠在注射 ADR 后表现出更严重的肾小球病变和足细胞损伤。相比之下，小鼠中 AEP 的特异性增强可防止 ADRN。在体外，人足细胞中 AEP 的敲低和过度表达揭示了 AEP 作为细胞骨架调节剂的细胞保护作用。此外，转凝胶蛋白（一种调节肌动蛋白动力学的肌动蛋白结合蛋白）被 AEP 切割，从而去除了其肌动蛋白结合调节域。与天然全长转基因蛋白相比，截短的转基因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 与足细胞细胞骨架稳态之间的联系，这表明 AEP 在蛋白尿疾病中具有潜在的治疗作用。
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.