Slug enables redox-sensitive trans-activation of LRP1 by COUP-TFII: Implication in antifibrotic intervention in the kidneys

Excessive fibrogenesis in the kidney causes structural and functional damages and is considered a hallmark event in end-stage renal diseases (ESRD). During renal fibrosis, resident fibroblasts undergo profound changes to become myofibroblasts. In the present study we investigated the involvement of Slug (encoded by Snai2) in this process. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in mice. Cellular transcriptome was evaluated by RNA-seq. We report that Slug expression was up-regulated during fibroblast-myofibroblast transition (FMyT) in vivo and in vitro. Slug knockdown attenuated TGF-β induced FMyT in primary renal fibroblasts and ameliorated renal fibrosis in mice. RNA-seq analysis revealed that Slug promoted FMyT by enabling key pro-fibrogenic transcription factors including the orphan nuclear receptor COUP-TFII. Mechanistically, Slug enhanced intracellular ROS levels by modulating the expression of redox-related genes. Elevated ROS levels in turn stimulated transcription of LDL receptor related protein 1 (Lrp1) by COUP-TFII. Importantly, both a COUP-TFII antagonist and an Lrp1 neutralization antibody mitigated renal fibrosis in mice. Our data support a role for Slug in regulating FMyT and renal fibrosis.