Hemodynamic disruption triggers glomerular barrier injury via endothelial glycocalyx degradation in nephrotic syndrome.

Nephrotic syndrome (NS) is characterized by heavy proteinuria and is frequently accompanied by a hypercoagulable, hemorheologically abnormal state. Although glomerular filtration barrier (GFB) failure is central to proteinuria, the contribution of altered microhemodynamic cues to endothelial barrier injury remains incompletely defined. The endothelial glycocalyx (EG) is both a permeability barrier and a mechanosensor of fluid shear stress (FSS). We combined an adriamycin (ADR)-induced NS rat model with vascular-on-a-chip (VOAC) and glomerulus-on-a-chip (GOAC) platforms. In vivo, coagulation, hemorheology, EG structure and components, inflammatory adhesion molecules, and urinary protein excretion were assessed, with prednisone acetate and sulodexide used as mechanistically distinct comparators. In vitro, endothelial cells were exposed to defined flow-rate conditions to isolate the effect of reduced mechanical stimulation on EG integrity, cytoskeletal organization, inflammatory activation, and GOAC permeability. ADR-treated rats developed hypercoagulability and increased blood viscosity together with marked EG loss and proteinuria. Sulodexide ameliorated hemorheological abnormalities and restored the integrity of the EG, whereas prednisone acetate predominantly reduced proteinuria and inflammatory adhesion-molecule expression. In the chip models, stepwise reductions in perfusion flow rate were associated with progressive EG loss, cytoskeletal disorganization, endothelial activation, and increased glomerular barrier permeability. These complementary models support reduced flow-associated mechanical stimulation as a plausible contributor to EG dysfunction and glomerular barrier leakage in NS. These data did not confirm that ADR-induced injury was entirely mediated by hemodynamic alterations; rather, they uncovered an EG-centered mechanobiological pathway that may operate alongside direct toxic and inflammatory insults.