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Acetyl-CoA synthetase 2 induces pyroptosis and inflammation of renal epithelial tubular cells in sepsis-induced acute kidney injury by upregulating the KLF5/NF-κB pathway.
- Source :
-
Cell communication and signaling : CCS [Cell Commun Signal] 2024 Mar 21; Vol. 22 (1), pp. 187. Date of Electronic Publication: 2024 Mar 21. - Publication Year :
- 2024
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Abstract
- Background: Pyroptosis of the renal tubular epithelial cells (RTECs) and interstitial inflammation are central pathological characteristics of acute kidney injury (AKI). Pyroptosis acts as a pro-inflammatory form of programmed cell death and is mainly dependent on activation of the NLRP3 inflammasome. Previous studies revealed that acetyl-CoA synthetase 2 (ACSS2) promotes inflammation during metabolic stress suggesting that ACSS2 might regulate pyroptosis and inflammatory responses of RTECs in AKI.<br />Methods and Results: The expression of ACSS2 was found to be significantly increased in the renal epithelial cells of mice with lipopolysaccharide (LPS)-induced AKI. Pharmacological and genetic strategies demonstrated that ACSS2 regulated NLRP3-mediated caspase-1 activation and pyroptosis through the stimulation of the KLF5/NF-κB pathway in RTECs. The deletion of ACSS2 attenuated renal tubular pathological injury and inflammatory cell infiltration in an LPS-induced mouse model, and ACSS2-deficient mice displayed impaired NLRP3 activation-mediated pyroptosis and decreased IL-1β production in response to the LPS challenge. In HK-2 cells, ACSS2 deficiency suppressed NLRP3-mediated caspase-1 activation and pyroptosis through the downregulation of the KLF5/NF-κB pathway. The KLF5 inhibitor ML264 suppressed NF-κB activity and NLRP3-mediated caspase-1 activation, thus protecting HK-2 cells from LPS-induced pyroptosis.<br />Conclusion: Our results suggested that ACSS2 regulates activation of the NLRP3 inflammasome and pyroptosis by inducing the KLF5/NF-κB pathway in RTECs. These results identified ACSS2 as a potential therapeutic target in AKI.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Acetyl Coenzyme A metabolism
Caspase 1 metabolism
Epithelial Cells metabolism
Inflammasomes metabolism
Inflammation metabolism
Ligases metabolism
Lipopolysaccharides pharmacology
NF-kappa B metabolism
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Pyroptosis
Acute Kidney Injury metabolism
Sepsis complications
Sepsis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1478-811X
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell communication and signaling : CCS
- Publication Type :
- Academic Journal
- Accession number :
- 38515158
- Full Text :
- https://doi.org/10.1186/s12964-024-01556-3