Abstract
BackgroundIdiopathic membranous nephropathy (IMN) is a cause of nephrotic syndrome that is increasing in incidence but has unclear pathogenesis. Urinary peptidomics is a promising technology for elucidating molecular mechanisms underlying diseases. Dysregulation of the proteolytic system is implicated in various diseases. Here, we aimed to conduct urinary peptidomics to identify IMN-related proteases.ResultsPeptide fingerprints indicated differences in naturally produced urinary peptide components among 20 healthy individuals, 22 patients with IMN, and 15 patients with other kidney diseases. In total, 1,080 peptide-matched proteins were identified, 279 proteins differentially expressed in the urine of IMN patients were screened, and 32 proteases were predicted; 55 of the matched proteins were also differentially expressed in the kidney tissues of IMN patients, and these were mainly involved in the regulation of proteasome-, lysosome-, and actin cytoskeleton-related signaling pathways. The 32 predicted proteases showed abnormal expression in the glomeruli of IMN patients based on Gene Expression Omnibus databases. Western blot revealed abnormal expression of calpain, matrix metalloproteinase 14, and cathepsin S in kidney tissues of patients with IMN.ConclusionsThis work shown the calpain/matrix metalloproteinase/cathepsin axis might be dysregulated in IMN. Our study is the first to systematically explore the role of proteases in IMN by urinary peptidomics, which are expected to facilitate discovery of better biomarkers for IMN.
Highlights
Idiopathic membranous nephropathy (IMN) is a cause of nephrotic syndrome that is increasing in incidence but has unclear pathogenesis
We aimed to elucidate the biological processes and signaling pathways involved in IMN-related protein dysregulation and tissue injury by analyzing naturally produced urinary peptides differentially expressed in IMN patients, identifying proteins matched to these peptides, and predicting and validating the proteases involved in the production of these peptides
This study proved that proteases uniquely dysregulated in IMN may be involved with urinary peptide production and that several proteases may be the driving factors of disease progression, which should be studied further
Summary
Idiopathic membranous nephropathy (IMN) is a cause of nephrotic syndrome that is increasing in incidence but has unclear pathogenesis. Urinary peptidomics is a promising technology for elucidating molecular mechanisms underlying diseases. In 2009, an antiphospholipase A2 receptor (anti-PLA2R) antibody was discovered in the sera of IMN patients [1]. Since it has been used in the diagnosis and therapeutic targeting of IMN, with about 70–80 % of patients being positive for this marker [5]. The mechanism underlying anti-PLA2R antibody production in these patients has not been fully clarified. In this context, Lin et al BMC Genomics (2021) 22:852 the main goal is to unravel the pathogenic molecular mechanism underlying kidney damage
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