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Abstract: FR-PO1071

The Role of SRY-box Transcription Factor 4 in Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Du, Hao, UConn Health, Farmington, Connecticut, United States
  • Jiao, Baihai, UConn Health, Farmington, Connecticut, United States
  • Tran, Melanie, UConn Health, Farmington, Connecticut, United States
  • Song, Bo, UConn Health, Farmington, Connecticut, United States
  • Wang, Yanlin, UConn Health, Farmington, Connecticut, United States

Chronic kidney disease (CKD) is a widely prevalent disorder around the world, which affects over 10% adults. The pathological feature of CKD is renal fibrosis, characterized by the excessive production and deposition of extracellular matrix (ECM). The production and accumulation of ECM is partly due to tubular epithelial cell (TEC) dedifferentiation. However, the molecular mechanisms underlying TEC dedifferentiation are not fully understood. In this study, we investigated the role of SRY-box transcription factor 4 (SOX4) in regulating TEC dedifferentiation during the development of CKD.


We generated SOX4 conditional knockout mice by crossing SOX4 floxed mice with tamoxifen-inducible CAG-CreER mice. CAG-Cre+/-SOX4f/f mice were given tamoxifen to induce SOX4 deletion (SOX4GKO). CAG-Cre-/-SOX4f/f mice received the same dose of tamoxifen and used as controls (SOX4CON). Both SOX4CON and SOX4GKO mice were subjected to unilateral ureteral obstruction (UUO). Kidneys were harvested at 10 days after UUO injury. Kidney sections were prepared and stained for histological and immunological analysis. Western blot analysis and immunostaining were performed to detect the levels of signaling molecules, fibronectin, collagen type I, and alpha-SMA in the kidneys. Sirius red staining was performed to detect total collagen deposition in the kidney. Cultured TECs were employed to examine the role and molecular mechanisms of SOX4 in the regulation of TEC dedifferentiation in vitro.


The expression of SOX4 was increased in TEC after UUO injury. In response to obstructive injury, SOX4CON mice exhibited TEC dedifferentiation with senescence and G2/M arrest, fibroblast activation and developed substantial total collagen deposition and ECM protein production in the kidney. Global SOX4 deficiency significantly alleviated TEC dedifferentiation, suppressed fibroblast activation, and reduced total collagen deposition and ECM protein production in the kidney with UUO injury. Furthermore, knockdown SOX4 by shRNA inhibited TEC dedifferentiation in cultured TEC in response to TGF-β1. Mechanically, SOX4 facilitated TGF-β1-Smad3 signaling to promote TEC dedifferentiation.


Our results demonstrate that SOX4 plays an essential role in the development of renal fibrosis by regulating TEC dedifferentiation and fibroblast activation. Therefore, SOX4 may serve as a novel therapeutic target for CKD.


  • NIDDK Support