MassIVE MSV000098667

Partial Public PXD066707

Fibrotic remodeling drives chronic kidney disease in organic acidurias, role of TGFbeta mediated extracellular matrix deposition

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Description

Propionic aciduria (PA uria) and methylmalonic aciduria (MMA uria) are rare inborn errors of metabolism caused by defects in the propionate catabolic pathway. 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 was further amplified under metabolic stress conditions. Transforming growth factor beta (TGFbeta) signaling was identified as a key profibrotic pathway. Pharmacological inhibition of the TGFbeta 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 TGFbeta signaling, also reversed the enhanced ECM deposition. This is the first study to mechanistically link ECM remodeling and TGFbeta 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. [doi:10.25345/C5TM72D5F] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: propionic acuduria, methylmalonic aciduria, chronic kidney disease, fibrosis, extracellular matrixc, TGF-beta signaling, renal epithelial cells ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Dr. Dr. Anke Schumann, Faculty of Medicine, Freiburg University Hospital, Germany
Submitting User: Stholen
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