Kidney Week

Abstract: TH-PO0241

Fn14 Mediates Failed Epithelial Repair in Repeated Low-Dose Cisplatin Nephrotoxicity

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Lee, Katie, University of Hawai'i at Manoa, Honolulu, Hawaii, United States

Katie Lee, PhD

• Glibetic, Natalija, University of Hawai'i at Manoa, Honolulu, Hawaii, United States

Natalija Glibetic, PhD

• Villiger, Ross, University of Hawai'i at Manoa, Honolulu, Hawaii, United States

Ross Villiger

• Fogelgren, Ben, University of Hawai'i at Manoa, Honolulu, Hawaii, United States

Ben Fogelgren, PhD

• Ortega, Michael, University of Hawai'i at Manoa, Honolulu, Hawaii, United States

Michael Ortega, PhD

Background

Chronic kidney disease (CKD) is characterized by a progressive decline in renal function, often resulting from persistent and repeated injury. The mechanisms in the repair response that dictate successful or failed resolution remain incompletely defined. The non-canonical NF-κB inflammatory pathway is activated under chronic stress and orchestrates cell survival and tissue remodeling. Here, we investigate whether targeting the non-canonical NF-κB receptor Fn14 attenuates chronic inflammation and fibrotic injury in the CKD repair response.

Methods

Wildtype (WT) and Fn14-knockout (Fn14-KO) mice were treated with cisplatin (10mg/kg body weight, i.p.) on days 0, 7, and 21. Kidneys were harvested on day 28 for immunohistochemical and spatial transcriptomic analyses. Smooth muscle cells were identified using alpha-smooth muscle actin (a-SMA), epithelial cells by pan-cytokeratin (PanCK), and S1/S2 proximal tubule cells by sodium-glucose cotransporter 2 (SGLT2). Spatial transcriptomics data were generated using the Nanostring GeoMx Digital Spatial profiler (DSP) platform using the mouse Whole Transcriptome Panel (WTA).

Results

Spatial transcriptomics revealed tissue-specific responses to cisplatin-induced nephrotoxicity. Overall, the Sglt2^- tubules of WT cisplatin-treated mice showed higher expression of kidney injury markers (KIM-1), markers of epithelial failed repair (VCAM-1, CK8), and tubule dedifferentiation (Vim, reduced Lrp2) compared to vehicle controls and Fn14-KO mice, while Sglt2⁺ tubules were relatively protected. Fn14-KO attenuated apoptotic signaling and mitigated epithelial cell loss after cisplatin exposure. Pro-fibrotic transcripts and collagen deposition were also reduced in Fn14-KO mice compared to WT after cisplatin treatment, in line with lower macrophage and myofibroblast populations.

Conclusion

These findings highlight the pathological role of non-canonical NF-κB signaling in promoting a tissue-specific failed repair phenotype. Fn14 ablation attenuates cisplatin-induced inflammatory and pro-fibrotic signaling pathways and reduces macrophage infiltration to the kidney. Spatial transcriptomics reveals tubule segments that sustain epithelial injury and are vulnerable to failed repair. These results present Fn14 as a promising therapeutic target against chronic inflammation in CKD progression.

Acknowledgment

This study was funded by NIH NIDDK R21DK133754 and NIGMS P20GM113134 to M.O.

Funding

• NIDDK Support