Dexmedetomidine attenuates lipopolysaccharide-induced renal cell fibrotic phenotypic changes by inhibiting necroinflammation via activating α2-adrenoceptor: A combined randomised animal and in vitro study - 27/04/24
Abstract |
Background |
Acute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α2-adrenoreceptor (AR) agonist, has cytoprotective and “anti-” inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models.
Methods |
C57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10 mg/kg) alone, LPS with Dex (25 μg/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500 μg/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1 μg/ml) alone, LPS and Dex (1 μM), transforming growth factor-beta 1 (TGF-β1) (5 ng/ml) alone, TGF-β1 and Dex, with or without Atip (100 μM) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined.
Results |
Dex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-β1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation.
Conclusions |
Dex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α2-AR activation in the renal tubular cells. The “anti-fibrotic” and cytoprotective properties and its clinical use of Dex need to be further studied.
Le texte complet de cet article est disponible en PDF.Abbreviations : CKD, ECM, EndoMT, EMT, TECs, AKI, S-AKI, DAMPs, Dex, LPS, α2-AR, Atip, GIS, TIS, H&E staining, HK2 cells, ECACC, TGF-β1, PBST, α-SMA, P-MLKL, NLRP3, DAPI, LDS, PVDF, GSDMD, JNK, GAPDH, PI, SD, TNF-α, HMGB-1, HSPs, RAGE, UUO, CoQ10, G-proteins, IRI, SMAD 3, TBM
Keywords : Dexmedetomidine, Acute kidney injury, Chronic kidney disease, Epithelial-mesenchymal transition, Necroinflammation, Sepsis
Plan
Vol 174
Article 116462- mai 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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