Overexpression of Corin Ameliorates Kidney Fibrosis through Inhibition of Wnt/-Catenin Signaling in Mice

The Wnt/13-catenin pathway represents a promising therapeutic target for mitigating kidney fibrosis. Corin possesses the homologous ligand binding site [Frizzled-cysteine-rich domain (Fz-CRD)] similar to Frizzled proteins, which act as receptors for Wnt. The Fz-CRD has been found in eight different proteins, all of which, except for corin, are known to bind Wnt and regulate its signal transmission. We hy-pothesized that corin may inhibit the Wnt/13-catenin signaling pathway and thereby reduce fibro-genesis. Reduced expression of corin along with the increased activity of Wnt/13-catenin signaling was found in unilateral ureteral obstruction (UUO) and ureteral ischemia/reperfusion injury (UIRI) models. In vitro, corin bound to the Wnt1 through its Fz-CRDs and inhibit the Wnt1 function responsible for activating 13-catenin. Transforming growth factor-131 inhibited corin expression, accompanied by activation of 13-catenin; conversely, overexpression of corin attenuated the fibrotic effects of trans-forming growth factor-131. In vivo, adenovirus-mediated overexpression of corin attenuated the pro-gression of fibrosis, which was potentially associated with the inhibition of Wnt/13-catenin signaling and the down-regulation of its target genes after UUO and UIRI. These results suggest that corin acts as an antagonist that protects the kidney from pathogenic Wnt/13-catenin signaling and from fibrosis following UUO and UIRI. (Am J Pathol 2024, 194: 101-120; https://doi.org/10.1016/ j.ajpath.2023.09.008)