Micheliolide ameliorates lipopolysaccharide-induced acute kidney injury through suppression of NLRP3 activation by promoting mitophagy via Nrf2/PINK1/Parkin axis

Jul 1, 2024International immunopharmacology

Micheliolide reduces sudden kidney damage caused by inflammation by boosting removal of damaged mitochondria through the Nrf2/PINK1/Parkin pathway

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Abstract

Micheliolide (MCL) improved renal injury in a sepsis-associated acute kidney injury (SA-AKI) mouse model.

MCL enhanced cell viability and suppressed cell death in LPS-treated kidney cells.
Inflammatory cytokine levels decreased with MCL treatment in these cells.
MCL improved mitochondrial function as indicated by reduced mitochondrial damage.
MCL reduced the activation of the NLRP3 inflammasome by promoting mitophagy.
Deficiency of the protein Nrf2 diminished the protective effects of MCL on inflammasome activation and mitophagy.
Inhibition of Nrf2 with ML385 yielded similar results in SA-AKI mice.

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BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) represents a frequent complication of in critically ill patients. The objective of this study is to illuminate the potential protective activity of Micheliolide (MCL) and its behind mechanism against SA-AKI.

METHODS: The protective potential of MCL on SA-AKI was investigated in lipopolysaccharide (LPS) treated HK2 cells and SA-AKI mice model. The mitochondrial damage was determined by detection of reactive oxygen species and membrane potential. The Nrf2 silencing was achieved by transfection of Nrf2-shRNA in HK2 cells, and Nrf2 inhibitor, ML385 was employed in SA-AKI mice. The mechanism of MCL against SA-AKI was evaluated through detecting hallmarks related to inflammation, mitophagy and Nrf2 pathway via western blotting, immunohistochemistry, and enzyme linked immunosorbent assay.

RESULTS: MCL enhanced viability, suppressed apoptosis, decreased inflammatory cytokine levels and improved mitochondrial damage in LPS-treated HK2 cells, and ameliorated renal injury in SA-AKI mice. Moreover, MCL could reduce the activation of NLRP3 inflammasome via enhancing mitophagy. Additionally, Nrf2 deficiency reduced the suppression effect of MCL on NLRP3 inflammasome activation and blocked the facilitation effect of MCL on mitophagy in LPS-treated HK2 cells, the consistent is true for ML385 treatment in SA-AKI mice.

CONCLUSIONS: MCL might target Nrf2 and further reduce the NLRP3 inflammasome activation via enhancing mitophagy, which alleviated SA-AKI.

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Micheliolide ameliorates lipopolysaccharide-induced acute kidney injury through suppression of NLRP3 activation by promoting mitophagy via Nrf2/PINK1/Parkin axis

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