Downregulation of PARD6B Is Associated with Irreversible Podocyte Damage in FSGS

Background: Focal segmental glomerulosclerosis (FSGS) often presents treatment resistance, necessitating further elucidation of its pathophysiology. Podocytes, the glomerular epithelial cells, maintain homeostasis through polarity regulation, but the role of polarity-related factors in FSGS remains poorly understood. We analyzed the expression of polarity-related factors in isolated glomeruli from human FSGS using Nephroseq, an omics analysis database for kidney diseases. As a result, we found that PARD6B was significantly downregulated in FSGS compared to normal controls, along with CRB2, which is a causative gene for hereditary FSGS. Since PARD6B is mainly expressed in podocytes within the glomerulus, this suggests a potential association with podocyte injury. This study aims to investigate the functional role of PARD6B in the pathogenesis of FSGS. Methods: We evaluated PARD6B expression in isolated glomeruli from podocyte injury mouse models induced by adriamycin or LPS. Tamoxifen-inducible podocyte-specific PARD6B-deficient mice were generated, and urine protein and renal pathology were assessed. In vitro functional analyses were performed using human podocyte cell lines treated with TNF-α or PARD6B siRNA. Results: Glomeruli isolated from podocyte-damaged mouse models exhibited significantly reduced PARD6B expression. Tamoxifen-induced podocyte-specific PARD6B-deficient mice showed severe proteinuria, podocyte swelling, epithelial cell hyperplasia, segmental sclerosis, and diffuse epithelial cell foot processes effacement, resembling human FSGS. Reduced nephrin expression/ abnormal localization and increased detached podocytes were also observed. In vitro, TNFα-treated human podocytes displayed significantly reduced PARD6B expression. Human podocytes treated with PARD6B siRNA demonstrated significant cell death, though no effects on the actin cytoskeleton were noted. Conclusion: These findings suggest that reduced PARD6B expression is associated with irreversible podocyte injury and progression of FSGS. Funding: Private Foundation Support