THIOREDOXIN-DEFICIENT RATS AS A TRANSLATIONAL MODEL FOR CHRONIC KIDNEY DISEASE: MITOCHONDRIAL DYSFUNCTION DRIVES PROGRESSIVE RENAL FAILURE THROUGH OXIDATIVE STRESS-MEDIATED PATHWAYS

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Abstract Title *

THIOREDOXIN-DEFICIENT RATS AS A TRANSLATIONAL MODEL FOR CHRONIC KIDNEY DISEASE: MITOCHONDRIAL DYSFUNCTION DRIVES PROGRESSIVE RENAL FAILURE THROUGH OXIDATIVE STRESS-MEDIATED PATHWAYS

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Co-author 1

Mamoru Ouchida ouchidam@okayama-u.ac.jp Okayama University Molecular Oncology Okayama Japan *

Co-author 2

Haruhito Uchida hauchida@okayama-u.ac.jp Okayama University Nephrology Okayama Japan -

Co-author 3

Shinya Toyokuni toyokuni.shinya.t4@f.mail.nagoya-u.ac.jp Nagoya University Pathology and Biological Responses Nagoya Japan -

Co-author 4

Tomoji Mashimo mashimo@ims.u-tokyo.ac.jp University of Tokyo Animal Genetics Tokyo Japan -

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Introduction

Chronic kidney disease (CKD) affects millions globally, yet therapeutic options remain limited due to incomplete understanding of disease mechanisms. While oxidative stress and mitochondrial dysfunction are implicated in CKD pathogenesis, translational models bridging molecular mechanisms to clinical phenotypes are lacking. Thioredoxin (Trx), encoded by Txn1, maintains cellular redox homeostasis and represents a potential therapeutic target.

Methods

We characterized lifelong phenotypes of Txn1-F54L mutant rats with ~33% normal Trx activity, generated via N-ethyl-N-nitrosourea mutagenesis and validated by CRISPR/Cas9 editing. Comprehensive translational analyses included clinical biochemistry, histopathology, electron microscopy, RNA-sequencing, and cytokine profiling to establish disease mechanisms and clinical relevance.

Results

Txn1-F54L rats spontaneously developed progressive CKD with survival times of 110-119 days (homozygotes) and 303-346 days (heterozygotes). Clinical manifestations—elevated blood urea nitrogen, hypoalbuminemia, hypercholesterolemia, hypertension, and arterial sclerosis—recapitulated human CKD. Histopathology revealed tubular injury, interstitial fibrosis, and glomerulosclerosis. Transcriptomic analysis identified 3,418 differentially expressed genes enriched in immune activation and fibrosis pathways. Proximal tubular mitochondrial dysfunction accompanied oxidative stress accumulation and activation of multiple regulated cell death pathways (apoptosis, necroptosis, pyroptosis). Elevated serum interleukin-1β, interleukin-6, and interferon-γ confirmed systemic inflammation.

Conclusion

This study establishes mechanistic links between thioredoxin deficiency, oxidative stress-mediated mitochondrial dysfunction, and progressive CKD. The Txn1 mutant rat provides a clinically relevant translational platform for developing oxidative stress-targeted therapeutics, potentially advancing precision medicine approaches for CKD prevention and treatment.

Kewords