Dexmedetomidine attenuates lipopolysaccharide-induced renal cell fibrotic phenotypic changes by inhibiting necroinflammation via activating α2-adrenoceptor: A combined randomised animal and in vitro study.
Biomed Pharmacother
; 174: 116462, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38513598
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) (10â¯mg/kg) alone, LPS with Dex (25⯵g/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500⯵g/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1⯵g/ml) alone, LPS and Dex (1⯵M), transforming growth factor-beta 1 (TGF-ß1) (5â¯ng/ml) alone, TGF-ß1 and Dex, with or without Atip (100⯵M) 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-ß1 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibrose
/
Receptores Adrenérgicos alfa 2
/
Dexmedetomidina
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Agonistas de Receptores Adrenérgicos alfa 2
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Camundongos Endogâmicos C57BL
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Biomed Pharmacother
Ano de publicação:
2024
Tipo de documento:
Article