Acid Sphingomyelinase and Ceramide Signaling Pathway Mediates Nicotine-Induced NLRP3 Inflammasome Activation and Podocyte Injury.
Study Goal
The researchers aimed to determine whether acid sphingomyelinase (Asm) and ceramide signaling mediate nicotine-induced Nlrp3 inflammasome activation and podocyte damage.
Results Summary
Nicotine increased Asm expression, ceramide production, and podocyte damage markers, which were attenuated by amitriptyline pretreatment. Nicotine also increased cell permeability, oxidative stress, and apoptosis, effects that were similarly reduced by amitriptyline.
Population
Podocytes (in vitro study)
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
Nicotine treatment | increase | Asm expression | podocytes | - | significantly increased | #1 |
Nicotine treatment | increase | ceramide production | podocytes | - | significantly increased | #2 |
amitriptyline | decrease | nicotine-induced Asm expression | podocytes | - | significantly attenuated | #3 |
amitriptyline | decrease | nicotine-induced ceramide production | podocytes | - | significantly attenuated | #4 |
Nicotine treatment | increase | colocalization of NLRP3 with Asc | podocytes | - | increased | #5 |
Nicotine treatment | increase | colocalization of Nlrp3 with caspase-1 | podocytes | - | increased | #6 |
Nicotine treatment | increase | IL-1β production | podocytes | - | increased | #7 |
Nicotine treatment | increase | caspase-1 activity | podocytes | - | increased | #8 |
Nicotine treatment | increase | desmin expression | podocytes | - | increased | #9 |
amitriptyline | decrease | nicotine-induced colocalization of NLRP3 with Asc | podocytes | - | abolished | #10 |
amitriptyline | decrease | nicotine-induced colocalization of Nlrp3 with caspase-1 | podocytes | - | abolished | #11 |
amitriptyline | decrease | nicotine-induced IL-1β production | podocytes | - | abolished | #12 |
amitriptyline | decrease | nicotine-induced caspase-1 activity | podocytes | - | abolished | #13 |
amitriptyline | decrease | nicotine-induced desmin expression | podocytes | - | abolished | #14 |
Nicotine treatment | decrease | podocin expression | podocytes | - | significantly decreased | #15 |
amitriptyline | decrease | nicotine-induced podocin reduction | podocytes | - | attenuated | #16 |
Nicotine treatment | increase | cell permeability | podocytes | - | significantly increased | #17 |
Nicotine treatment | increase | O2 production | podocytes | - | significantly increased | #18 |
Nicotine treatment | increase | apoptosis | podocytes | - | significantly increased | #19 |
amitriptyline | decrease | nicotine-induced cell permeability | podocytes | - | significantly attenuated | #20 |
amitriptyline | decrease | nicotine-induced O2 production | podocytes | - | significantly attenuated | #21 |
amitriptyline | decrease | nicotine-induced apoptosis | podocytes | - | significantly attenuated | #22 |
Background: Recent studies have shown that Nlrp3 inflammasome activation is importantly involved in podocyte dysfunction induced by nicotine. The present study was designed to test whether acid sphingomyelinase (Asm) and ceramide signaling play a role in mediating nicotine-induced Nlrp3 inflammasome activation and subsequent podocyte damage. Methods and Results: Nicotine treatment significantly increased the Asm expression and ceramide production compared to control cells. However, prior treatment with amitriptyline, an Asm inhibitor significantly attenuated the nicotine-induced Asm expression and ceramide production. Confocal microscopic and biochemical analyses showed that nicotine treatment increased the colocalization of NLRP3 with Asc, Nlrp3 vs. caspase-1, IL-1β production, caspase-1 activity, and desmin expression in podocytes compared to control cells. Pretreatment with amitriptyline abolished the nicotine-induced colocalization of NLRP3 with Asc, Nlrp3 with caspase-1, IL-1β production, caspase-1 activity and desmin expression. Immunofluorescence analyses showed that nicotine treatment significantly decreased the podocin expression compared to control cells. However, prior treatment with amitriptyline attenuated the nicotine-induced podocin reduction. In addition, nicotine treatment significantly increased the cell permeability, O2 production, and apoptosis compared to control cells. However, prior treatment with amitriptyline significantly attenuated the nicotine-induced cell permeability, O2 production and apoptosis in podocytes. Conclusions: Asm is one of the important mediators of nicotine-induced inflammasome activation and podocyte injury. Asm may be a therapeutic target for the treatment or prevention of glomerulosclerosis associated with smoking.