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J Lipid Res. 2017 Jun;58(6):1080-1090. doi: 10.1194/jlr.M072587. Epub 2017 Apr 12.

NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury.

Author information

1
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
2
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA pin-lan.li@vcuhealth.org.

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-1β 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.

KEYWORDS:

inflammation; kidney; lipid mediators; lipid rafts; lipoxygenase; nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3; podocyte; ω-3 fatty acid

PMID:
28404641
PMCID:
PMC5454504
DOI:
10.1194/jlr.M072587
[Indexed for MEDLINE]
Free PMC Article

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