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Our earlier study further demonstrated that podocytes share additional similarities with immune cells, as they can synthesize and secrete the active form of cathepsin C \u2013 an enzyme that controls the activation of neutrophil serine proteases (NSPs). In this study, we established that podocytes synthesize neutrophil elastase (NE), proteinase 3 (PR 3), and cathepsin G (CatG) but also release their active forms into the extracellular environment. We found that NSPs contribute to podocyte dysfunction upon inflammation induction by PMA and under conditions of insulin insensitivity. Moreover, actin cytoskeleton rearrangement and increased albumin permeability of the podocyte monolayer were triggered by nucleotide\u2010binding and oligomerization domain\u2010containing protein 2 (NOD2) activation via muramyl dipeptide (MDP), which consequently enhanced NE and PR 3 activity. Notably, silencing the\n                    <jats:italic>ELANE<\/jats:italic>\n                    gene, which encodes NE, exerted a protective effect on podocytes even after NOD2 activation. These findings indicate that NSPs, especially NE, contribute to podocyte dysfunction in diabetes and diabetic kidney disease, a condition characterized by chronic inflammation and insulin resistance.\n                  <\/jats:p>","DOI":"10.1002\/jcp.70116","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T07:42:08Z","timestamp":1764834128000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Role of Neutrophil Elastase in Podocyte Dysfunction Induced by High Glucose, PMA, and MDP"],"prefix":"10.1002","volume":"240","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5166-7444","authenticated-orcid":false,"given":"Tomasz","family":"Kulesza","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology Medical University of Gdansk and University of Gdansk Gdansk Pomorskie Poland"},{"name":"Laboratory of 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