TY - JOUR T1 - Proteolytic Cleavage by Matriptase Exacerbating Kidney Injury: a Novel Therapeutic Target JF - bioRxiv DO - 10.1101/843607 SP - 843607 AU - Shota Ozawa AU - Masaya Matsubayashi AU - Hitoki Nanaura AU - Motoko Yanagita AU - Kiyoshi Mori AU - Katsuhiko Asanuma AU - Nobuyuki Kajiwara AU - Kazuyuki Hayashi AU - Hiroshi Ohashi AU - Masato Kasahara AU - Hideki Yokoi AU - Hiroaki Kataoka AU - Eiichiro Mori AU - Takahiko Nakagawa Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/15/843607.abstract N2 - Chronic kidney disease (CKD) is a progressive disease, and podocyte injury is a potential mechanism. We found that Matriptase was activated at podocytes in CKD patients and mice while a Matriptase inhibitor slowed the progression of mouse kidney disease. The mechanism could be accounted for by an imbalance favoring Matriptase over its cognate inhibitor, hepatocyte growth factor activator inhibitor type 1 (HAI-1), as conditional depletion of HAI-1 in podocytes accelerates podocyte injury. Intriguingly, the N-terminal of Podocin (Podocin-N), as a consequence of Matriptase cleavage of Podocin, translocates to nucleoli. These results suggest that aberrant activation of Matriptase would cause podocyte injury, and a targeting Matriptase could be a novel therapeutic strategy for CKD patients.Significant statement Chronic kidney disease (CKD) is a progressive disease. If podocytes, which are specialized cells of the kidney glomerulus that wrap around capillaries, are injured, kidney injury is exacerbated. Thus, a therapeutic strategy to addressing CKD would be to block podocyte injury. The present study provides evidence that Matriptase cleaves Podocin, a component of podocyte slit membrane, and the N-terminal of podocin translocates to nucleoli, causing kidney injury. Our findings show that the N-terminal of Podocin plays an efficient role for cell fate in podocytes. In addition, the inhibition of Matriptase would be a potential therapeutic target for CKD. ER -