Regulation of Fn14 stability by SCFFbxw7α during septic acute kidney injury.
Am J Physiol Renal Physiol
; 316(6): F1273-F1281, 2019 06 01.
Article
em En
| MEDLINE
| ID: mdl-31017010
ABSTRACT
Acute kidney injury (AKI) initiated by sepsis remains a thorny problem despite recent advancements in its clinical management. Having been found to be activated during AKI, fibroblast growth factor-inducible molecule 14 (Fn14) may be a potential therapeutic target because of its involvement in the molecular basis of injury. Here, we report that LPS induces apoptosis of mouse cortical tubule cells mediated by Fn14, for which simultaneous Toll-like receptor (TLR)4 activation is required. Mechanistically, TLR4 activation by lipopolysaccharide, through disassociating E3 ligase SCFFbxw7α from Fn14, dismantles Lys48-linked polyubiquitination of Fn14 and stabilizes it. Pharmacological deactivation of Fn14 with monoclonal antibody ITEM-2 provides effective protection against lethal sepsis and AKI in mice. Our study underscores an adaptive mechanism whereby TLR4 regulates SCFFbxw7α-dependent Fn14 stabilization during inflammatory tubular damage and further supports investigation of targeting Fn14 in clinical trials of patients with septic AKI.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sepse
/
Injúria Renal Aguda
/
Proteína 7 com Repetições F-Box-WD
/
Receptor de TWEAK
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Túbulos Renais
/
Macrófagos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Am J Physiol Renal Physiol
Assunto da revista:
FISIOLOGIA
/
NEFROLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China