A Novel Role of Neutrophil Elastase in Podocyte Dysfunction Induced by High Glucose, PMA, and MDP.

Podocytes are not only the key regulators of glomerular filtration barrier dynamics but also exhibit immunological properties. They are capable of antigen presentation and possess a receptor system recognizing pathogen-associated molecular patterns. 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 - 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-binding and oligomerization domain-containing protein 2 (NOD2) activation via muramyl dipeptide (MDP), which consequently enhanced NE and PR 3 activity. Notably, silencing the ELANE 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.