Acta pharmacologica Sinica, 2022-01, Vol.43 (1), p.86-95
2022
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Caspase-11 promotes NLRP3 inflammasome activation via the cleavage of pannexin1 in acute kidney disease
- Ist Teil von
- Acta pharmacologica Sinica, 2022-01, Vol.43 (1), p.86-95
- Ort / Verlag
- Singapore: Springer Singapore
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) in clinic. The activation of NLRP3 inflammasome is associated with inflammation and renal injury in I/R-induced AKI. In the current study we explored the molecular and cellular mechanisms for NLRP3 inflammasome activation following renal I/R. Mice were subjected to I/R renal injury by clamping bilateral renal pedicles. We showed that I/R injury markedly increased caspase-11 expression and the cleavage of pannexin 1 (panx1) in the kidneys accompanied by NLRP3 inflammasome activation evidenced by the activation of caspase-1 and interlukin-1β (IL-1β) maturation. In Casp-11 −/− mice, I/R-induced panx1 cleavage, NLRP3 inflammasome activation as well as renal functional deterioration and tubular morphological changes were significantly attenuated. In cultured primary tubular cells (PTCs) and NRK-52E cells, hypoxia/reoxygenation (H/R) markedly increased caspase-11 expression, NLRP3 inflammasome activation, IL-1β maturation and panx1 cleavage. Knockdown of caspase-11 attenuated all those changes; similar effects were observed in PTCs isolated from Casp-11 −/− mice. In NRK-52E cells, overexpression of caspase-11 promoted panx1 cleavage; pretreatment with panx1 inhibitor carbenoxolone or knockdown of panx1 significantly attenuated H/R-induced intracellular ATP reduction, extracellular ATP elevation and NLRP3 inflammasome activation without apparent influence on H/R-induced caspase-11 increase; pretreatment with P2X7 receptor inhibitor AZD9056 also attenuated NLRP3 inflammasome activation. The above results demonstrate that the cleavage of panx1 by upregulated caspase-11 is involved in facilitating ATP release and then NLRP3 inflammasome activation in I/R-induced AKI. This study provides new insight into the molecular mechanism of NLRP3 inflammasome activation in AKI.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1671-4083eISSN: 1745-7254DOI: 10.1038/s41401-021-00619-2Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8724289
- Format
- –
- Schlagworte
- Acute Kidney Injury - metabolism, Acute Kidney Injury - pathology, Animals, Biomedical and Life Sciences, Biomedicine, Caspase-1, Caspase-11, Caspases, Initiator - deficiency, Caspases, Initiator - metabolism, Cells, Cultured, Connexins - metabolism, Dose-Response Relationship, Drug, Hypoxia, IL-1β, Immunology, Inflammasomes, Inflammasomes - metabolism, Internal Medicine, Ischemia, Kidney diseases, Kidneys, Medical Microbiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Structure, Nerve Tissue Proteins - metabolism, NLR Family, Pyrin Domain-Containing 3 Protein - metabolism, Pharmacology/Toxicology, Reperfusion, Reperfusion Injury - metabolism, Reperfusion Injury - pathology, Structure-Activity Relationship, Vaccine