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Transforming growth factor-β-mediated fibrotic remodeling drives chronic kidney disease in methylmalonic aciduria and propionic aciduria - identification of a new therapeutic target

Propionic aciduria (PA-uria) and methylmalonic aciduria (MMA-uria) are caused by defects in propionate catabolism. While chronic kidney disease (CKD) is a well-established complication in MMA-uria, renal involvement in PA-uria has only come into focus more recently, and the underlying mechanisms rem...

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Main Authors: Zeyer, Karina (Author) , Tholen, Stefan (Author) , Schilling, Oliver (Author) , Gerling, Leonie (Author) , Morath, Marina (Author) , Kölker, Stefan (Author) , Nyström, Alexander (Author) , Spiekerkoetter, Ute (Author) , Schumann, Anke (Author)
Format: Article (Journal)
Language:English
Published: November 2025
In: Journal of inherited metabolic disease
Year: 2025, Volume: 48, Issue: 6, Pages: 1-14
ISSN:1573-2665
DOI:10.1002/jimd.70111
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/jimd.70111
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/jimd.70111
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Author Notes:Karina A. Zeyer, Stefan Tholen, Oliver Schilling, Leonie Gerling, Marina Morath, Stefan Kölker, Alexander Nyström, Ute Spiekerkoetter, Anke Schumann
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Summary:Propionic aciduria (PA-uria) and methylmalonic aciduria (MMA-uria) are caused by defects in propionate catabolism. While chronic kidney disease (CKD) is a well-established complication in MMA-uria, renal involvement in PA-uria has only come into focus more recently, and the underlying mechanisms remain poorly understood. We investigated human renal epithelial cells from patients with PA-uria, MMA-uria, and healthy controls under metabolic stress, induced by methylmalonic acid, methylcitric acid, high-protein, or isoleucine/valine-enriched media. Proteomic profiling revealed significant enrichment of extracellular matrix (ECM)-related pathways in PA-uria cells. Both PA-uria and MMA-uria cells exhibited increased deposition of fibronectin and collagen fibers, which were further amplified under metabolic stress conditions. Transforming growth factor beta (TGF-β) signaling was identified as a key pro-fibrotic pathway. Pharmacological inhibition of the TGF-β receptor signaling normalized fibronectin and collagen deposition in both PA-uria and MMA-uria cells. Treatment with losartan, an angiotensin II type 1 receptor blocker known to modulate TGF-β signaling, also reversed the enhanced ECM deposition. This is the first study to mechanistically link ECM remodeling and TGF-β signaling to CKD pathogenesis in both PA-uria and MMA-uria. Our findings highlight fibrotic remodeling as a shared pathogenic feature and suggest that losartan, a widely available and well-tolerated drug, could be repurposed to mitigate renal fibrosis in these disorders.
Item Description:Zuerst veröffentlicht: 25. Oktober 2025
Gesehen am 03.12.2025
Physical Description:Online Resource
ISSN:1573-2665
DOI:10.1002/jimd.70111

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