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Acid-sensing ion channel 1a exacerbates renal ischemia–reperfusion injury through the NF-κB/NLRP3 inflammasome pathway
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Acid-sensing ion channel 1a exacerbates renal ischemia–reperfusion injury through the NF-κB/NLRP3 inflammasome pathway
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Acid-sensing ion channel 1a exacerbates renal ischemia–reperfusion injury through the NF-κB/NLRP3 inflammasome pathway
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Journal Article
Acid-sensing ion channel 1a exacerbates renal ischemia–reperfusion injury through the NF-κB/NLRP3 inflammasome pathway
2023
Overview
Ischemia-reperfusion injury (IRI) is the main cause of acute kidney injury (AKI), and there is no effective therapy. Microenvironmental acidification is generally observed in ischemic tissues. Acid-sensing ion channel 1a (ASIC1a) can be activated by a decrease in extracellular pH which mediates neuronal IRI. Our previous study demonstrated that, ASIC1a inhibition alleviates renal IRI. However, the underlying mechanisms have not been fully elucidated. In this study, we determined that renal tubule-specific deletion of ASIC1a in mice (ASIC1afl/fl/CDH16cre) attenuated renal IRI, and reduced the expression of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, and IL-1β. Consistent with these in vivo results, inhibition of ASIC1a by the specific inhibitor PcTx-1 protected HK-2 cells from hypoxia/reoxygenation (H/R) injury, and suppressed H/R-induced NLRP3 inflammasome activation. Mechanistically, the activation of ASIC1a by either IRI or H/R induced the phosphorylation of NF-κB p65, which translocates to the nucleus and promotes the transcription of NLRP3 and pro-IL-1β. Blocking NF-κB by treatment with BAY 11-7082 validated the roles of H/R and acidosis in NLRP3 inflammasome activation. This further confirmed that ASIC1a promotes NLRP3 inflammasome activation, which requires the NF-κB pathway. In conclusion, our study suggests that ASIC1a contributes to renal IRI by affecting the NF-κB/NLRP3 inflammasome pathway. Therefore, ASIC1a may be a potential therapeutic target for AKI.Key messagesKnockout of ASIC1a attenuated renal ischemia-reperfusion injury.ASIC1a promoted the NF-κB pathway and NLRP3 inflammasome activation.Inhibition of the NF-κB mitigated the NLRP3 inflammasome activation induced by ASIC1a.
