NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury.
J Lipid Res
; 58(6): 1080-1090, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-28404641
ABSTRACT
The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been implicated in podocyte injury and glomerular sclerosis during hyperhomocysteinemia (hHcys). However, it remains unclear whether the NLRP3 inflammasome can be a therapeutic target for treatment of hHcys-induced kidney injury. Given that DHA metabolites-resolvins have potent anti-inflammatory effects, the present study tested whether the prototype, resolvin D1 (RvD1), and 17S-hydroxy DHA (17S-HDHA), an intermediate product, abrogate hHcys-induced podocyte injury by targeting the NLRP3 inflammasome. In vitro, confocal microscopy demonstrated that 17S-HDHA (100 nM) and RvD1 (60 nM) prevented Hcys-induced formation of NLRP3 inflammasomes, as shown by reduced colocalization of NLRP3 with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or caspase-1. Both DHA metabolites inhibited Hcys-induced caspase-1 activation and interleukin-1ß production. However, DHA had no significant effect on these Hcys-induced changes in podocytes. In vivo, DHA lipoxygenase metabolites substantially inhibited podocyte NLRP3 inflammasome formation and activation and consequent glomerular sclerosis in mice with hHcys. Mechanistically, RvD1 and 17S-HDHA were shown to suppress Hcys-induced formation of lipid raft redox signaling platforms and subsequent O2·- production in podocytes. It is concluded that inhibition of NLRP3 inflammasome activation is one of the important mechanisms mediating the beneficial action of RvD1 and 17S-HDHA on Hcys-induced podocyte injury and glomerular sclerosis.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácidos Docosa-Hexaenoicos
/
Inflamassomos
/
Proteína 3 que Contém Domínio de Pirina da Família NLR
/
Glomérulos Renais
Limite:
Animals
Idioma:
En
Revista:
J Lipid Res
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Vaticano