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 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.