A novel spontaneous rat model of chronic kidney disease with mitochondrial dysfunction driven by thioredoxin insufficiency

Background: Chronic kidney disease (CKD) is a global health burden with high prevalence and poor prognosis. Although oxidative stress and mitochondrial dysfunction have been implicated in its pathogenesis, in vivo causal evidence remains limited. Thioredoxin (Trx), encoded by Txn1, is a redox-active protein that plays a central role in controlling oxidative stress and maintaining intracellular redox homeostasis.
Methods: To address this gap, we investigated the lifelong phenotypes of Txn1-F54L mutant rats harboring approximately one-third of the normal Trx activity. These rats were generated via N-ethyl-N-nitrosourea mutagenesis and validated by clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 genome editing. Comprehensive analyses included biochemical testing, histopathology, immunohistochemistry, transmission electron microscopy, RNA-sequencing, western blotting, and cytokine profiling.
Results: Txn1-F54L mutant rats spontaneously developed progressive CKD, with median survival times of 110–119 days for homozygotes and 303–346 days for heterozygotes. Their clinical features—elevated blood urea nitrogen, hypoalbuminemia, hypercholesterolemia, hypertension, and arterial medial sclerosis—closely resembled those of human CKD. Histopathological evaluation revealed extensive tubular injury, interstitial fibrosis, and glomerulosclerosis. Transcriptomic profiling identified 3,418 differentially expressed genes significantly enriched in immune activation and fibrosis pathways. Mitochondrial dysfunction was prominent in proximal tubules, accompanied by oxidative stress accumulation and concurrent activation of regulated cell death pathways (apoptosis, necroptosis, and pyroptosis). Elevated serum levels of interleukin-1β, interleukin-6, and interferon-γ indicated systemic inflammation.
Conclusions: Our findings demonstrate that lifelong Trx deficiency induces oxidative stress–mediated mitochondrial dysfunction and regulated cell death, leading to inflammation and progressive CKD. This study establishes the Txn1 mutant rat as a valuable spontaneous CKD model, providing translational insights and a platform for developing therapeutic strategies targeting oxidative stress–induced pathways.