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Abstract: FR-PO980

Fn14 Knockout Ameliorates Cisplatin-Induced Nephrotoxicity in Mice by Reducing Inflammation, Preventing Tubular Cell Death, and Decreasing Renal Fibrosis

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Villiger, Ross, University of Hawai'i at Manoa, Honolulu, Hawaii, United States
  • Ortega, Michael, Queen's Medical Center, Honolulu, Hawaii, United States
  • Harrison-Chau, Malia H., University of Hawai'i at Manoa, Honolulu, Hawaii, United States
  • Patwardhan, Geetika Yi, University of Hawai'i at Manoa, Honolulu, Hawaii, United States
  • Fogelgren, Ben, University of Hawai'i at Manoa, Honolulu, Hawaii, United States
Background

Tumor necrosis factor receptor superfamily 12A (TNFRSF12a), also known as Fn14, is a transmembrane cytokine receptor often upregulated in damaged tissues or in malignancies. Fn14 has a single known ligand, the cytokine TWEAK, although at high concentrations, Fn14 can self-oligomerize. Primarily associated with activating the non-canonical NF-kB pathway, TWEAK-Fn14 signaling can also contribute to multiple downstream cellular pathways, including cell death and fibrosis, depending on contributions from other TNF receptors and the cell microenvironment. We detected strong upregulation of the Fn14 gene in stressed cells of the kidney and urinary tract, and the goal of this study was to determine if Fn14 signaling contributes to the pathogenesis of chronic kidney disease (CKD).

Methods

With CRISPR-Cas gene editing, we generated a novel Fn14-knockout mouse (Fn14-KO). We challenged male and female wild-type C57BL/6J and Fn14-KO mice to a repeated low dose regimen of cisplatin to model CKD. After the dosing regimen, we analyzed blood biochemistry, renal histopathology, and renal gene expression using the NanoString nCounter platform.

Results

The Fn14-KO mouse demonstrated complete absence of Fn14 protein, was fertile, and lacked gross abnormalities. Compared to wild-type mice, Fn14-KO mice had reduced cisplatin-induced nephrotoxicity assessed by blood biochemistry and renal histopathology. Cisplatin-treated wild type mice showed substantial renal tubular cell death, which was absent in Fn14-KO kidneys. Transcriptomic data revealed significant reductions in genes associated with inflammation and fibrosis in the Fn14-KO kidneys, which correlated with histopathological findings.

Conclusion

Fn14 signaling contributed to tubular cell death and renal fibrosis in this mouse model of CKD. Blocking TWEAK-Fn14 signaling may help ameliorate cisplatin-induced nephrotoxicity and other forms of CKD, although targeting the Fn14 receptor may be more effective if it can self-activate with high expression.

Funding

  • NIDDK Support