Abstract
Chronic kidney disease is a global health concern characterized by maladaptive repair processes leading to kidney fibrosis. Following injury, early alterations in the extracellular matrix precede the development of kidney fibrosis and represent potential therapeutic targets to improve kidney repair. In this context, studies from our laboratory and others have shown that the matricellular protein SMOC2 can be targeted to decrease inflammation and tubulointerstitial fibrosis following kidney injury. The tubular epithelial cells (TECs), which are abundant and particularly susceptible to injury, play a central role in maladaptive repair; however, whether SMOC2 affects their functionality after kidney injury has not been explored. In this study, we show that SMOC2 localizes to the basement membrane of injured TECs across three murine models of kidney injury. Our in vitro studies demonstrate that SMOC2 induces a partial epithelial-to-mesenchymal (EMT) transition of TECs. We further demonstrate that its extracellular calcium-binding domain mediates binding to the decellularized extracellular matrix and mediates most of its effects on TECs. Mechanistically, SMOC2 promotes partial EMT effects through an integrin-dependent pathway. Together, these findings provide new mechanistic insight into how SMOC2 drives maladaptive repair by modulating TEC behavior and identify its calcium-binding domain as a key functional mediator.
Authors
Schrodinger Cenatus, Peng Gao, Nathalie Henley, Caroline Lamarche, Xue-Song Liu, Frédérick A. Mallette, Jonatan Barrera-Chimal, Casimiro Gerarduzzi
