{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:27:53Z","timestamp":1792520873270,"version":"4.5.0"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["431984000 \u2013 CRC 1453 Nephrogenetics"],"award-info":[{"award-number":["431984000 \u2013 CRC 1453 Nephrogenetics"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Propionic aciduria (PA\u2010uria) and methylmalonic aciduria (MMA\u2010uria) are caused by defects in propionate catabolism. While chronic kidney disease (CKD) is a well\u2010established complication in MMA\u2010uria, renal involvement in PA\u2010uria has only come into focus more recently, and the underlying mechanisms remain poorly understood. We investigated human renal epithelial cells from patients with PA\u2010uria, MMA\u2010uria, and healthy controls under metabolic stress, induced by methylmalonic acid, methylcitric acid, high\u2010protein, or isoleucine\/valine\u2010enriched media. Proteomic profiling revealed significant enrichment of extracellular matrix (ECM)\u2010related pathways in PA\u2010uria cells. Both PA\u2010uria and MMA\u2010uria cells exhibited increased deposition of fibronectin and collagen fibers, which were further amplified under metabolic stress conditions. Transforming growth factor beta (TGF\u2010\u03b2) signaling was identified as a key pro\u2010fibrotic pathway. Pharmacological inhibition of the TGF\u2010\u03b2 receptor signaling normalized fibronectin and collagen deposition in both PA\u2010uria and MMA\u2010uria cells. Treatment with losartan, an angiotensin II type 1 receptor blocker known to modulate TGF\u2010\u03b2 signaling, also reversed the enhanced ECM deposition. This is the first study to mechanistically link ECM remodeling and TGF\u2010\u03b2 signaling to CKD pathogenesis in both PA\u2010uria and MMA\u2010uria. Our findings highlight fibrotic remodeling as a shared pathogenic feature and suggest that losartan, a widely available and well\u2010tolerated drug, could be repurposed to mitigate renal fibrosis in these disorders.<\/jats:p>","DOI":"10.1002\/jimd.70111","type":"journal-article","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T15:04:21Z","timestamp":1761404661000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Transforming Growth Factor\u2010\u03b2\u2010Mediated Fibrotic Remodeling Drives Chronic Kidney Disease in Methylmalonic Aciduria and Propionic Aciduria\u2014Identification of a New Therapeutic Target"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0640-2528","authenticated-orcid":false,"given":"Karina A.","family":"Zeyer","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Adolescent Medicine and Neonatology Faculty of Medicine, Medical Center \u2013 University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Tholen","sequence":"additional","affiliation":[{"name":"Institute for Surgical Pathology, Medical Center \u2013 University of Freiburg\/Medical Faculty \u2013 University of Freiburg  Freiburg Germany"},{"name":"Proteomics Platform \u2013 Core Facility (ProtCF) Medical Center \u2013 University of Freiburg\/Medical Faculty \u2013 University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Schilling","sequence":"additional","affiliation":[{"name":"Institute for Surgical Pathology, Medical Center \u2013 University of Freiburg\/Medical Faculty \u2013 University of Freiburg  Freiburg Germany"},{"name":"Proteomics Platform \u2013 Core Facility (ProtCF) Medical Center \u2013 University of Freiburg\/Medical Faculty \u2013 University of Freiburg  Freiburg 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