Proteolytic cleavage of Podocin by Matriptase exacerbates podocyte injury [Cell Biology]

Podocyte injury is a critical step toward the progression of renal disease and is often associated with a loss of slit diaphragm proteins, including Podocin. Although there is a possibility that the extracellular domain of these slit diaphragm proteins can be a target for a pathological proteolysis, the precise mechanism driving the phenomenon remains unknown. Here we show that Matriptase, a membrane-anchored protein, was activated at podocytes in CKD patients and mice, whereas Matriptase inhibitors 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), because conditional depletion of HAI-1 in podocytes accelerated podocyte injury in mouse model. Matriptase was capable of cleaving Podocin, but such a reaction was blocked by either HAI-1 or dominant-negative Matriptase. Furthermore, the N terminus of Podocin, as a consequence of Matriptase cleavage of Podocin, translocated to nucleoli, suggesting that the N terminus of Podocin might be involved in the process of podocyte injury. Given these observations, we propose that the proteolytic cleavage of Podocin by Matriptase could potentially cause podocyte injury and that targeting Matriptase could be a novel therapeutic strategy for CKD patients.

Source: Journal of Biological Chemistry - November 20, 2020 Category: Chemistry Authors: Shota Ozawa, Masaya Matsubayashi, Hitoki Nanaura, Motoko Yanagita, Kiyoshi Mori, Katsuhiko Asanuma, Nobuyuki Kajiwara, Kazuyuki Hayashi, Hiroshi Ohashi, Masato Kasahara, Hideki Yokoi, Hiroaki Kataoka, Eiichiro Mori, Takahiko Nakagawa Tags: Molecular Bases of Disease Source Type: research