Loss of Fn14 Reduces Cisplatin-Induced Maladaptive Inflammatory and Fibrotic Gene Expression and Limits Downstream Tubular Damage.

Persistent and repeated damage contribute to chronic kidney disease (CKD) progression, with repair responses diverging between successful resolution and failed repair. In the transition towards failed repair, renal tubules develop a maladaptive phenotype which establishes conditions that sustain chronic inflammation leading to fibrosis. To define regulators of this inflection point, we investigated the role of non-canonical NF-B signaling, a persistent inflammatory pathway that is activated under chronic stress. Using CRISPR-Cas9 gene editing, we generated a novel Fn14 knockout (Fn14-KO) mouse, as Fn14 is one of a limited number of receptors identified that engages the non-canonical NF-B pathway. Male and female wildtype and Fn14-KO mice underwent a repeated low-dose cisplatin regimen to model CKD. Post-treatment, we analyzed blood biochemistry, renal histopathology, and renal gene expression via the NanoString nCounter platform. Although renal injury was observed by histology and gene expression (KIM-1) in both wildtype and Fn14-KO mice following cisplatin treatment, transcriptional profiles suggested that Fn14-KO mice exhibited relative preservation of proximal tubule differentiation and survival markers. In contrast, wildtype kidneys displayed hallmark transcriptional features of maladaptive repair, including tubular dedifferentiation, apoptosis, complement activation, and fibrogenesis. Collectively, these findings suggest that Fn14-mediated non-canonical NF-B signaling is a critical driver of the transition to maladaptive repair, positioning it as a potential therapeutic target to mitigate CKD progression.