Visfatin‐Induced Lipid Raft Redox Signaling Platforms and Hyperpermeability in Glomerular Endothelial Cells

Abstract

Adipocytokines have been reported to contribute to the glomerular injury during obesity or diabetes mellitus. However, the mechanisms mediating the actions of various adipocytokines on the kidney remained elusive. The present study was performed to determine whether acid sphingomyelinase (ASM)‐ceramide signaling pathway is involved in local oxidative stress in glomerular endothelial cells (GECs) induced by adipocytokines such as visfatin and adiponectin. Using confocal microscope, visfatin but not adiponectin was found to increase lipid rafts (LRs) clustering on the membrane of GECs in a dose‐dependent manner. Upon visfatin stimulation ASM activity was increased, an aggregation of ceramide or NADPH oxidase subunits, gp91phox and p47phox was observed in LR clusters, which was blocked by prior treatment with LR disruptor filipin, adiponectin, ASM inhibitor amitriptyline or ASM siRNA. Corresponding to aggregation of LR clustering with NADPH subunits in GECs upon stimulation with visfatin, superoxide (O2·−) production was significantly increased (2.7 folds) as measured by ESR. Functionally, visfatin treatment significantly increased the GEC permeability and this action of visfatin was blocked by inhibition of LR redox signaling platform formation. In conclusion, the injurious effect of visfatin, but not adiponection on the glomerular endothelium is associated with the formation of LR redox signaling platforms via LR clustering, which increases the glomerular permeability by disruption of microtubule network in GECs (supported by NIH grants HL‐091464, HL‐75316 and DK54927).