Wang Min, Liu Hanlin, Zhang Mengxi, Niu Xiaohan, Sun Min, Wang Fang, Ni Yingyin, Hong Tao, Zhang Wei, Dang Suying
Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics (East China Normal University), School of Life Science, East China Normal University, China.
Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochem Biophys Res Commun. 2025 Mar 1;750:151386. doi: 10.1016/j.bbrc.2025.151386. Epub 2025 Jan 23.
The glomerular filtration barrier (GFB) has a unique spatial structure, including porous capillary endothelial cells, glomerular basal membrane (GBM) and highly specialized podocytes. This special structure is essential for the hemofiltration process of nephrons. GBM is the central meshwork structure of GFB formed by the assembly and fusion of various extracellular matrix (ECM) macromolecules, such as laminins and collagens, which undergo isoform transformation and maturation that may require precise regulation by metalloproteinases. However, the role of metalloproteinase in GFB integrity remains elusive. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) gene family members are known for their roles in ECM remodeling. In this study, we found that ADAMTS18 was secreted by capillary endothelial cell within the glomeruli of human fetal kidney and mouse kidney. Adamts18 knockout (Adamts18) mice exhibited early proteinuria with GFB dysplasia, including podocyte invagination surrounded by glomerular capillary network and microvillus of podocytes. Mechanistically, ADAMTS18 regulated the isoform transformation and maturation of GBM macromolecules. The levels of mature LAMA5 isoform and fibronectin were significantly lower in Adamts18 glomeruli than in Adamts18 glomeruli. Co-immunoprecipitation (IP) results showed that the LAMA5 fragment (5XAU) was a novel interacting protein of ADAMTS18 and could be pulled down by ADAMTS18. These new findings shed light on the biological role of metalloproteinase in GFB integrity and related kidney diseases.
肾小球滤过屏障（GFB）具有独特的空间结构，包括有孔的毛细血管内皮细胞、肾小球基底膜（GBM）和高度特化的足细胞。这种特殊结构对于肾单位的血液滤过过程至关重要。GBM是GFB的中央网状结构，由各种细胞外基质（ECM）大分子如层粘连蛋白和胶原蛋白组装融合而成，这些大分子会经历亚型转化和成熟，这可能需要金属蛋白酶的精确调控。然而，金属蛋白酶在GFB完整性中的作用仍不清楚。含血小板反应蛋白基序的解聚素和金属蛋白酶（ADAMTSs）基因家族成员以其在ECM重塑中的作用而闻名。在本研究中，我们发现ADAMTS18由人胎儿肾脏和小鼠肾脏肾小球内的毛细血管内皮细胞分泌。Adamts18基因敲除（Adamts18 -/-）小鼠表现出早期蛋白尿伴GFB发育异常，包括足细胞内陷被肾小球毛细血管网络包围以及足细胞微绒毛形成。机制上，ADAMTS18调节GBM大分子的亚型转化和成熟。Adamts18 -/-肾小球中成熟的LAMA5亚型和纤连蛋白水平显著低于Adamts18 +/+肾小球。免疫共沉淀（IP）结果表明，LAMA5片段（5XAU）是ADAMTS18的一种新型相互作用蛋白，可被ADAMTS18拉下。这些新发现揭示了金属蛋白酶在GFB完整性及相关肾脏疾病中的生物学作用。
