Recently we have shown that adipokine visfatin‐induced NLRP3 inflammasome activation contributes to podocyte injury. However, the molecular mechanisms of how visfatin‐induces the Nlrp3 inflammasome activation and podocyte damage still unknown. The present study tested whether ceramide and membrane raft (MR) redox signalling pathway plays a central role in visfatin‐induced inflammasomes formation and activation in podocytes. Using confocal microscopy, visfatin was found to increase MRs clustering in the membrane of podocytes in a dose dependent manner. Upon visfatin stimulation an aggregation of ASMase product, ceramide and NADPH oxidase subunits, gp91(phox) and p47(phox) was observed in the MR clusters, forming a MR redox signaling platform. The formation of this signalling platform was blocked by prior treatment with MR disruptor MCD, NOX inhibitor DPI, ASMase inhibitor amitriptyline. In addition, electron spin resonance (ESR) spectrometry analysis showed that visfatin treatment significantly increased the superoxide (O2·−) production compared to control cells. However, prior treatment with ASMase inhibitor amitriptyline significantly attenuated the visfatin‐induced superoxide production. Furthermore, immunofluorescence analysis demonstrated that visfatin treatment significantly decreased the podocin and nephrin expression (podocyte damage), and prior treatments with DPI, WEHD (inflammasome inhibitor), MCD and amitriptyline attenuated this visfatin‐induced podocin reduction. In conclusion, our results demonstrate that visfatin‐induced the ceramide production via ASMase and thereby stimulates membrane raft clustering in the membrane of podocytes to form redox signalling platforms by aggregation and activation of NADPH oxidase subunits, enhancing O2·− production and leading to Nlrp3 inflammasome formation and activation in podocytes and ultimate glomerular injury (supported by NIH grant, DK104031).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.