Abstract Chronic kidney disease (CKD) encompasses multiple pathogenic mechanisms manifested by inflammation, fibrosis, oxidative stress and cell death. We previously showed that circulating protein CD5L (or AIM) ameliorates acute kidney injury, so we explored its effect in a mouse model of unilateral ureteral obstruction (UUO)-induced renal fibrosis. Here, we show a unique kidney-protective pathway mediated by CD5L. CD5L is endocytosed into renal epithelial cells, where it reduces oxidative stress, decreasing cell injury and death. This effect is supported by both a cysteine-dependent direct antioxidant activity of CD5L and enhancement of Nrf2-associated antioxidant responses. In addition, our data suggest that suppression of sphingomyelinase activity and reduction of cellular ceramide may contribute, at least in part, to CD5L-associated augmentation of Nrf2 nuclear transport. These effects depend on the reactive cysteine residue on the CD5L surface. Consistent with these findings, recombinant CD5L treatment in UUO mice reduces sphingomyelinase activity, activates Nrf2, and lowers oxidative stress, alleviating inflammation, fibrosis, and kidney injury. Our findings uncover a novel antioxidant pathway mediated by CD5L with potential implications for CKD-associated fibrotic mechanisms.
Kudo et al. (Sat,) studied this question.