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bioRxiv · 10.1101/2023.08.14.553187

Txn1 mutation is a monogenic cause of chronic kidney disease associated with mitochondrial dysfunction in rats

Ohmori, I.·Ouchida, M.·Hada, Y.·Uchida, H. A.·Toyokuni, S.·Mashimo, T.
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Abstract

Oxidative stress plays a significant role in the progression of chronic kidney disease. Thioredoxin 1 (Txn1) is one of the enzymatic antioxidants to regulate redox balance. However, the molecular mechanisms by Txn1 affects renal homeostasis remain unclear. This study aimed at elucidating the pathophysiology of Txn1 mutations in renal function. We used rats with the Txn1-F54L mutation generated by N-ethyl-N-nitrosourea mutagenesis. Laboratory tests and pathological examinations were performed in wild-type (WT) rats and in rats with heterozygous and homozygous Txn1-F54L mutations. We performed RNA-seq analysis of the WT and homozygotes. To confirm phenotypic reproducibility, the Txn1-F54L mutation was generated in rats with different genetic backgrounds using CRISPR/Cas9 genome editing technology. Txn1-F54L mutant rats exhibited progressive albuminuria, hypoalbuminemia, hypercholesterolemia, and hypertension. Renal pathology revealed marked nephrosclerosis, tubular dilatation, interstitial fibrosis, and decreased number of mitochondria, mainly in the paroxysmal tubules. We confirmed a similar phenotype of chronic kidney disease (CKD) in different rat strains. RNA-seq showed the downregulation of mitochondria-related genes and significant upregulation of genes associated with inflammation, pyroptosis, apoptosis, and necroptosis in mutant rats. Our results show that the Txn1 mutation is a monogenic cause of CKD termination. The underlying pathology involves several regulated cell-death pathways. Thus, our study provides a new animal model of oxidative stress-induced CKD. Txn1-F54L mutant rats will aid in developing therapeutic strategies for CKD. Translational StatementWe found that the deficiency of thioredoxin (Txn1), which regulates oxidative stress, spontaneously caused chronic kidney disease (CKD) in rats. The Txn1-F54L (Adem) rat is a new model of CKD with complications such as anemia, hypertension, and cardiovascular disease. Renal pathology revealed nephrosclerosis, interstitial fibrosis, and mitochondrial damage. The molecular basis of the underlying pathologies included inflammation, pyroptosis, apoptosis, and necroptosis. These pathological changes are partially linked to renal diseases such as diabetic nephropathy, hypertensive nephrosclerosis, and ischemic reperfusion injury. Adem rats could help understand the common pathological mechanisms of these renal diseases and develop therapeutic strategies.

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Ohmori, I., Ouchida, M., Hada, Y., Uchida, H. A., Toyokuni, S., Mashimo, T.. 2023-08-15. Txn1 mutation is a monogenic cause of chronic kidney disease associated with mitochondrial dysfunction in rats. https://doi.org/10.1101/2023.08.14.553187

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