Proteolytic Cleavage by Matriptase Exacerbating Kidney Injury: a Novel Therapeutic Target

Ozawa, S.; Matsubayashi, M.; Nanaura, H.; Yanagita, M.; Mori, K.; Asanuma, K.; Kajiwara, N.; Hayashi, K.; Ohashi, H.; Kasahara, M.; Yokoi, H.; Kataoka, H.; Mori, E.; Nakagawa, T.

doi:10.1101/843607

bioRxiv · 10.1101/843607

Proteolytic Cleavage by Matriptase Exacerbating Kidney Injury: a Novel Therapeutic Target

Ozawa, S.·Matsubayashi, M.·Nanaura, H.·Yanagita, M.·Mori, K.·Asanuma, K.·Kajiwara, N.·Hayashi, K.·Ohashi, H.·Kasahara, M.·Yokoi, H.·Kataoka, H.·Mori, E.·Nakagawa, T.

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Abstract

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 statementChronic 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.

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Ozawa, S., Matsubayashi, M., Nanaura, H., Yanagita, M., Mori, K., Asanuma, K., Kajiwara, N., Hayashi, K., Ohashi, H., Kasahara, M., Yokoi, H., Kataoka, H., Mori, E., Nakagawa, T.. 2019-11-15. Proteolytic Cleavage by Matriptase Exacerbating Kidney Injury: a Novel Therapeutic Target. https://doi.org/10.1101/843607

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