Transforming Growth Factor‐β‐Mediated Fibrotic Remodeling Drives Chronic Kidney Disease in Methylmalonic Aciduria and Propionic Aciduria—Identification of a New Therapeutic Target

TL;DR

This study identifies TGF-β signaling as a driver of kidney disease in two metabolic disorders and suggests losartan as a potential treatment.

Contribution

The study is the first to mechanistically link ECM remodeling and TGF-β signaling to CKD in PA-uria and MMA-uria.

Findings

PA-uria and MMA-uria cells show increased fibronectin and collagen deposition under metabolic stress.

TGF-β signaling inhibition normalizes ECM deposition in both PA-uria and MMA-uria cells.

Losartan reverses enhanced ECM deposition by modulating TGF-β signaling.

Abstract

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.

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