Accelerated basement membrane remodeling and serum matrix fragments as biomarkers of fibrosis in Alport syndrome.
Abstract
Chronic kidney disease (CKD) is characterized by fibrosis. Alport syndrome, a common monogenic form of CKD caused by collagen type IV variants, leads to basement membrane defects and progressive fibrosis. Understanding extracellular matrix dynamics is crucial for identifying disease-specific biomarkers and optimizing therapeutic timing. We applied a discovery approach combining stable C-lysine metabolic labeling with proteomics, RNA sequencing, super-resolution imaging, and bioinformatics to define temporal and spatial kidney matrix dynamics in Alport mice. Transcriptomic profiling revealed enriched matrix degradation pathways and upregulated proteases, while C-lysine proteomics demonstrated altered abundance and accelerated turnover of basement membrane components. Super-resolution imaging confirmed matrix protein disorganization, and peptide location fingerprinting mapped damage modifications across ∼40 matrix proteins, predicting fragmentation in collagens, laminins, and nidogens. Predicted matrix fragments were detectable in serum from children with Alport variants versus healthy controls, linking basement membrane turnover and fibrosis with clinically accessible biomarkers for CKD and other fibrotic disorders.
