Visfatin-induced lipid raft redox signaling platforms and dysfunction in glomerular endothelial cells |
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Authors: | Krishna M Boini Chun Zhang Min Xia Wei-Qing Han Christopher Brimson Justin L Poklis Pin-Lan Li |
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Institution: | 1. Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, People''s Republic of China;2. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People''s Republic of China;1. Department of Nephrology, Nanjing Children''s Hospital, Nanjing Medical University, Nanjing, China;2. Institute of Pediatrics, Nanjing Medical University, Nanjing, China;3. Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, China;4. Division of Nephrology, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA |
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Abstract: | Adipokines have been reported to contribute to glomerular injury during obesity or diabetes mellitus. However, the mechanisms mediating the actions of various adipokines on the kidney remained elusive. The present study was performed to determine whether acid sphingomyelinase (ASM)-ceramide associated lipid raft (LR) clustering is involved in local oxidative stress in glomerular endothelial cells (GECs) induced by adipokines such as visfatin and adiponectin. Using confocal microscopy, visfatin but not adiponectin was found to increase LRs clustering in the membrane of GECs in a dose and time dependent manner. Upon visfatin stimulation ASMase activity was increased, and an aggregation of ASMase product, ceramide and NADPH oxidase subunits, gp91phox and p47phox was observed in the LR clusters, forming a LR redox signaling platform. The formation of this signaling platform was blocked by prior treatment with LR disruptor filipin, ASMase inhibitor amitriptyline, ASMase siRNA, gp91phox siRNA and adiponectin. Corresponding to LR clustering and aggregation of NADPH subunits, superoxide (O2?) production was significantly increased (2.7 folds) upon visfatin stimulation, as measured by electron spin resonance (ESR) spectrometry. Functionally, visfatin significantly increased the permeability of GEC layer in culture and disrupted microtubular networks, which were blocked by inhibition of LR redox signaling platform formation. In conclusion, the injurious effect of visfatin, but not adiponectin on the glomerular endothelium is associated with the formation of LR redox signaling platforms via LR clustering, which produces local oxidative stress resulting in the disruption of microtubular networks in GECs and increases the glomerular permeability. |
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