The secreted protease ADAMTS18 is a novel activator of latent TGF-β to exacerbate renal fibrosis

Renal fibrosis (RF) is an inevitable consequence of almost all forms of progressive chronic kidney disease (CKD). TGFβ is a powerful cytokine capable of dominating the fibrotic process. Targeting factors capable of activating latent TGF-β is a more effective and safe strategy to reduce TGF-β-induced fibrosis, but appropriate targets need to be identified. Here, we show that ADAMTS18/Adamts18 is significantly upregulated in the fibrotic kidneys of human CKD patients and mice. ADAMTS18 is primarily produced by renal tubular epithelial cells and fibroblasts during RF. Functionally, Adamts18 deletion inhibits epithelial-mesenchymal transition, inflammation, and collagen synthesis. Conversely, Adamts18 overexpression exacerbates progressive renal fibrosis. Mechanistically, the KPFR sequence in ADAMTS18 disrupts the latency-associated peptide (LAP) interaction with TGF-β and increases the release of mature TGF-β1. Blockage of ADAMTS18-mediated latent TGF-β activation by a tetrapeptide (LSKL) effectively reverses RF. Collectively, ADAMTS18 is a novel LAP-TGF-β1 activator with the potential to optimize CKD treatment strategies.