Potential Role of the Urokinase-Type Plasminogen Activator Receptor-Integrin β3 Axis in Podocyte Adhesion Instability and Loss.

Introduction: Podocyte detachment is a critical determinant of irreversible podocyte loss and progression of proteinuric glomerular diseases. Although altered glomerular hemodynamics are a hallmark of kidney diseases, it remains unclear how specific fluid mechanical forces contribute to podocyte adhesion failure and detachment in disease-relevant contexts. Methods: Renal biopsy specimens from patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and control kidneys were analyzed for urokinase-type plasminogen activator receptor (uPAR), integrin β3, and fibronectin (FN1) expression. Differentiated human podocytes were exposed to controlled fluid shear stress (FSS) using an orbital shear system. Podocyte retention, detachment, and F-actin cytoskeletal remodeling were quantified alongside biochemical assessments of downstream mechanotransduction signaling pathways through immunoblotting and quantitative image analysis. Integrin β3 inhibition and neutralizing antibodies were used as mechanistic probes. Results: Biopsy specimens showed disease-specific profiles-uPAR and integrin β3 were markedly upregulated in active MN and MCD glomeruli but attenuated and chronic lesion-like in FSGS. Conclusions: Immunologic or mechanical injury may induce the uPAR-integrin β3 axis, whereas sustained FSS amplifies it through FAK/JNK signaling, F-actin disruption, and detachment. Integrin β3 inhibition attenuated this cascade, supporting integrin-associated mechanotransduction as a strategy for preserving podocyte adhesion under altered glomerular hemodynamics.