The secreted protease ADAMTS18 links early isoform transformation and maturation of glomerular basement membrane macromolecules to the integrity of the glomerular filtration barrier

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.