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

ABSTRACT: 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.

INSTRUMENT(S): timsTOF fleX

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Dr. Anke Schumann

PROVIDER: MSV000098667 | MassIVE | Tue Jul 29 01:50:00 BST 2025

SECONDARY ACCESSION(S): PXD066707

REPOSITORIES: MassIVE

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Project description:The invasive and metastatic spread of ovarian cancer (OC) results from the cooperative interactions between cancer and stroma, which include acellular extracellular matrix (ECM) and cellular components, such as cancer-associated fibroblasts (CAFs). Soluble growth factors secreted by cancer and stromal cells contribute to stroma remodeling through the synthesis and modification of ECM proteins, providing a favorable environment for cancer cell dissemination. Within the OC, the peptide endothelin-1 (ET-1), through two G protein-coupled receptors, ET A R and ET B R, supports tumor growth and progression by acting on both cancer and stromal cells. Many of these effects rely on the functional and molecular link with the protein b-arrestin1 (b-arr1). However, the precise role of ET-1 in regulating the expression of ECM proteins by primary human ovarian fibroblasts (HOFs) remains unclear. In this study, we aimed to elucidate the regulatory role of ET-1 in the expression of type I collagen (Col1) and fibronectin 1 (FN1). We report a significant increase in the expression of both Col1 and FN1 in cells stimulated with ET-1, both at mRNA and protein levels, reaching the amounts of proteins found in ovarian CAFs. The observed effects are associated with the activation of both receptors since they are impaired by treatment with either ET A R or ET B R antagonists in HOFs and CAFs. Furthermore, they are particularly affected by the dual ET A R/ET B R antagonist bosentan, in vitro and in vivo models. At the molecular level, ET-1 activates the Col1 promoter and enhances the expression of this gene through the nuclear function of β-arr1. The change in transcriptome of HOFs silenced for β-arr1 was analyzed to confirm the molecular response triggered by β-arr1, which resulted in the upregulation of ECM remodeling and collagen deposition. In summary, these findings demonstrate that the ET-1 axis may contribute to the remodeling of the ECM and probably to the early stages of OC progression by modulating the expression of Col1 and FN1. The targeting of ET-1 signaling with ET A R/ET B R antagonists may impede HOFs’ ability to produce key ECM proteins in this tumor.

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

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