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A novel redox signalling axis mediates nicotine-induced podocyte injury
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DOI：10.3389/fphar.2026.1916699.png)
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Abstract
En 中文
IntroductionNicotine has been shown to induce Nlrp3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome activation; thereby contributing to podocyte injury. However; the molecular mechanisms underlying nicotine-induced Nlrp3 inflammasome activation and subsequent podocyte dysfunction remain largely unknown. The present study investigated whether membrane raft (MR)-associated redox signalling plays a critical role in nicotine-induced Nlrp3 inflammasome activation and podocyte injury.Methods and ResultsNicotine treatment induced membrane raft clustering in podocytes in a dose-dependent manner. Upon nicotine stimulation; the NADPH oxidase subunits gp91phox and p47phox were recruited and aggregated within membrane raft clusters; leading to the formation of a membrane raft redox signalling platform. The formation of this signalling platform was significantly inhibited by pretreatment with the membrane raft disruptor methyl-β-cyclodextrin (MCD); the NADPH oxidase inhibitor diphenyleneiodonium (DPI); or the acid sphingomyelinase (Asm) inhibitor amitriptyline. Nicotine also markedly enhanced the colocalization of Nlrp3 with ASC and caspase-1; indicating inflammasome assembly; and significantly increased caspase-1 activity; IL-1β production; desmin expression; podocyte permeability; and apoptosis compared with control cells. These effects were significantly attenuated by pretreatment with MCD; DPI; the caspase-1 inhibitor WEHD; or amitriptyline. Furthermore; immunofluorescence analysis demonstrated that nicotine significantly reduced podocin expression; whereas pretreatment with MCD; DPI; WEHD; or amitriptyline largely preserved podocin expression.ConclusionOur findings demonstrate that membrane raft-associated redox signalling serves as a critical upstream mechanism driving nicotine-induced NLRP3 inflammasome activation and podocyte injury.
Keywords:
smoking
inflammasome
podocytes
nicotine
membrane raft
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