Pathogenesis of Focal Segmental Glomerulosclerosis and Minimal Change Disease: Insights from Glomerular Proteomics

Podocyte injury is a hallmark of both focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD), ultimately reflected in foot process effacement and proteinuria. Triggers and pathogenic pathways leading to podocyte cytoskeleton rearrangements are, however, incompletely explained. Here, we aimed to contribute to the understanding of these pathways using tissue bottom-up proteomic profiling of laser-capture microdissected glomeruli from MCD and FSGS. Forty-six differentially expressed proteins were identified between the two groups (<i>p</i> < 0.05, |FC| ≥ 1.2). Pathway analysis showed that 16 out of 46 proteins were associated with the immune system, with E2 ubiquitin-conjugating enzyme (UBE2K) and complement factor H-related protein-1 (CFHR1) yielding the highest fold change in FSGS compared to MCD. The two target proteins were further validated through immunohistochemistry, confirming the podocyte localization of UBE2K and endothelial staining of CFHR. Additionally, several other differentially expressed proteins were linked to the cytoskeleton structure and its regulation. Our results point to the possibility that complement dysregulation may be the source of cytoskeleton rearrangement in FSGS.