New mutant rat model replicates human chronic kidney disease

Chronic kidney disease (CKD) is a major health burden affecting approximately one in ten adults globally. Even with improved treatments, many patients continue to have worsening loss of kidney function, resulting in the need for dialysis or transplantation. Oxidative stress and mitochondrial dysfunction have long been suspected to contribute to CKD, but direct evidence linking these processes to disease development has been limited.

Thioredoxin (Trx), a small, highly conserved oxidoreductase protein, is essential for counteracting oxidative stress and regulating cellular redox balance. Abnormal Trx expression is linked to a variety of illnesses, including cancer and autoimmune disorders. While oxidative stress plays a central role in the pathogenesis of CKD, the role of chronic Trx deficiency in initiating the disease is understudied.

To address this gap, a research team led by Professor Iori K. Ohmori from Okayama University sought to investigate the role of Trx deficiency in developing progressive CKD by inducing oxidative stress-mediated mitochondrial dysfunction and regulated cell death in Trx mutant rats. Dr. Mamoru Ouchida and Professor Haruhito Uchida from Okayama University, along with Professor Tomoji Mashimo from The University of Tokyo collaborated with Prof. Ohmori for this research work. The findings of this study were made available online on June 12, 2026, in the journal Translational Research.

"While the Txn1-F54L mutant rat was originally developed for nervous system-related research, we subsequently discovered that the presence of the Txn1 gene mutation also leads to the development of CKD. As Txn1 encodes Trx, the mutation reduced Trx activity to approximately one-third of normal levels," explained Prof. Ohmori. "This created a unique opportunity to examine the long-term effects of persistent antioxidant insufficiency."

Txn1-F54L mutant rats developed spontaneous CKD characterized by genotype-dependent severity. Homozygous mutants showed accelerated renal deterioration and markedly reduced survival, whereas heterozygous mutants displayed a delayed but progressive disease course consistent with CKD.

The rats displayed many hallmarks of human CKD, including elevated blood urea nitrogen, hypoalbuminemia, hypercholesterolemia, hypertension, and arterial medial sclerosis. Histopathological analysis of kidney tissue revealed extensive tubular injury, interstitial fibrosis, and glomerulosclerosis, pathological changes commonly observed in patients with advanced CKD.

To uncover the molecular mechanisms underlying disease development, the team performed transcriptomic profiling. In samples collected from the renal cortex, 3,418 genes showed altered expression patterns in mutant rat models, with strong enrichment observed for pathways associated with inflammation, fibrosis, and immune activation. At the same time, genes involved in mitochondrial function and energy production were markedly suppressed. The study also identified upregulation of several regulated cell death pathways, including apoptosis, necroptosis, and pyroptosis.

The study also showed a significant reduction in mitochondrial number as well as abnormal mitochondrial morphology in mutant rat models. These findings indicate that chronic Trx deficiency compromises mitochondrial integrity, potentially depriving kidney cells of the energy needed to maintain normal function.

These cellular events included elevated levels of inflammatory cytokines such as interleukin-1β, interleukin-6, and interferon-γ in the bloodstream, indicating that local kidney injury was linked to broader systemic inflammation. "The oxidative stress resulting from Trx insufficiency initiates a cascade in which mitochondrial dysfunction triggers cell death, inflammation, and ultimately progressive tissue fibrosis," explained Prof. Ohmori.

Existing animal models often replicate only selected aspects of CKD or rely on artificial injury methods. Prof. Ohmori highlights, "The rat model we developed naturally exhibits features resembling human CKD. The progression of the disease involves not only damage to kidney cells but also a complex interplay of inflammation and fibrosis."

By establishing a direct connection between impaired antioxidant defense, mitochondrial dysfunction, regulated cell death, and kidney failure, the study provides fresh insights into CKD pathogenesis. The findings also suggest that therapies aimed at restoring redox balance, protecting mitochondria, or modulating cell death pathways could represent promising approaches for slowing or preventing disease progression.