title: NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury.
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.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Guangbi
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Zhida
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Owais M
authors.initials: OM
authors.lastname: Bhat
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Justine M
authors.initials: JM
authors.lastname: Abais-Battad
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Sabena M
authors.initials: SM
authors.lastname: Conley
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Ritter
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA pin-lan.li@vcuhealth.org.
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
mesh_terms: D000818:Animals; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D058945:Lipoxygenases / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010084:Oxidation-Reduction; D050199:Podocytes / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C518399:resolvin D1; D004281:Docosahexaenoic Acids; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid; D058945:Lipoxygenases
keywords: inflammation; kidney; lipid mediators; lipid rafts; lipoxygenase; nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3; podocyte; ω-3 fatty acid