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Abstract: TH-PO937

Identification of C/EBPβ-TMIGD1 as a Novel Renoprotective Pathway

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Belghasem, Mostafa, Boston University School of Medicine, Boston, Massachusetts, United States
  • Tashjian, Joseph Y., Boston University, Boston, Massachusetts, United States
  • Roth, Daniel M., Boston University School of Medicine, Boston, Massachusetts, United States
  • Walker, Joshua A., Boston University School of Medicine, Boston, Massachusetts, United States
  • Richards, Sean, Boston University School of Medicine, Boston, Massachusetts, United States
  • Francis, Jean M., Boston University Medical Center, Boston, Massachusetts, United States
  • Rahimi, Nader, Boston University School of Medicine, Boston, Massachusetts, United States
  • Chitalia, Vipul C., Boston University School of Medicine, Boston, Massachusetts, United States
Background

The management of chronic kidney disease (CKD) patients lacks agents that protects functional renal mass, which predominantly consists of tubules. We recently identified transmembrane and immunoglobulin domain-containing 1 (TMIGD1) as a novel receptor expressed predominantly in the proximal tubular epithelial cells. TMIGD1 regulates epithelial cell adhesion and protects kidney epithelial cells from oxidative stress-induced cell injury in cell culture. While, TMIGD1 expression changes in acute kidney injury and chronic CKD mouse models, depending to the stage of disease the in vivo renoprotective function of TMIGD1 remains unknown.

Methods

TMIGD1 transcriptional regulation and promoter were characterized using electrophoretic mobility shift assay (EMSA). Expression of TMIGD1 and C/EBPb were examined in three discrete CKD models – unilateral ureteral obstruction (UUO), Adenine-induced CKD and remnant kidney model (RKM) model through immunofluorescence staining. CRSIPR/Cas9 TMIGD1 +/- mice were subjected to adenine-induced CKD model. Targetability of TMIGD1 was demonstrated using TMIGD1 blocking antibody.

Results

C/EBPβ strong interacts with TMIGD1 promoter and stimulates promoter activity of TMIGD1 in HEK-293 cells. C/EBPβ showed nuclear localization in normal renal tubular cells, however, it was lost with the induction of CKD and correlated with the downregulation of TMIGD1 in renal tubules. CRSIPR/Cas9 TMIGD1 +/-CKD mice showed a significantly lower kidney weight/body weight ratio suggesting a greater extent of renal atrophy compared to the wild type littermates. Pre-treatment of mice with a TMIGD1 blocking antibody augmented renal tubular damage.

Conclusion

We present C/EBPβ-TMIGD1 axis as a novel renoprotective pathway, which can be explored further to preserve the functional renal mass in CKD.