NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury. 2017

Guangbi Li, and Zhida Chen, and Owais M Bhat, and Qinghua Zhang, and Justine M Abais-Battad, and Sabena M Conley, and Joseph K Ritter, and Pin-Lan Li
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.

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.

UI MeSH Term Description Entries
D007678 Kidney Glomerulus A cluster of convoluted capillaries beginning at each nephric tubule in the kidney and held together by connective tissue. Glomerulus, Kidney
D008297 Male Males
D010084 Oxidation-Reduction A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). Redox,Oxidation Reduction
D004281 Docosahexaenoic Acids C22-unsaturated fatty acids found predominantly in FISH OILS. Docosahexaenoate,Docosahexaenoic Acid,Docosahexenoic Acids,Docosahexaenoic Acid (All-Z Isomer),Docosahexaenoic Acid Dimer (All-Z Isomer),Docosahexaenoic Acid, 3,6,9,12,15,18-Isomer,Docosahexaenoic Acid, 4,7,10,13,16,19-(All-Z-Isomer),Docosahexaenoic Acid, 4,7,10,13,16,19-(All-Z-Isomer), Cerium Salt,Docosahexaenoic Acid, 4,7,10,13,16,19-(All-Z-Isomer), Cesium Salt,Docosahexaenoic Acid, 4,7,10,13,16,19-(All-Z-Isomer), Potassium Salt,Docosahexaenoic Acid, 4,7,10,13,16,19-(Z,Z,Z,Z,Z,E-Isomer),Docosahexaenoic Acid, 4,7,10,13,16,19-Isomer,Docosahexaenoic Acid, 4,7,10,13,16,19-Isomer, Sodium Salt,Docosahexaenoic Acid, Sodium Salt,Acid, Docosahexaenoic,Acids, Docosahexaenoic,Acids, Docosahexenoic
D000071199 NLR Family, Pyrin Domain-Containing 3 Protein An NLR protein that contains an N-terminal PYRIN DOMAIN and ATP-binding site and 9 C-terminal LEUCINE-rich repeats; it is expressed primarily by MACROPHAGES. It is a core component of the INFLAMMASOME and directs its assembly in response to pathogen infection and damage-associated stimuli. Mutations in the NLRP3 gene are associated with FAMILIAL COLD AUTOINFLAMMATORY SYNDROME. Cold Autoinflammatory Syndrome 1 Protein,NACHT, LRR and PYD Domains-Containing Protein 3,NLRP3 Protein,NACHT, LRR and PYD Domains Containing Protein 3,NLR Family, Pyrin Domain Containing 3 Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D050199 Podocytes Highly differentiated epithelial cells of the visceral layer of BOWMAN CAPSULE of the KIDNEY. They are composed of a cell body with major CELL SURFACE EXTENSIONS and secondary fingerlike extensions called pedicels. They enwrap the KIDNEY GLOMERULUS capillaries with their cell surface extensions forming a filtration structure. The pedicels of neighboring podocytes interdigitate with each other leaving between them filtration slits that are bridged by an extracellular structure impermeable to large macromolecules called the slit diaphragm, and provide the last barrier to protein loss in the KIDNEY. Visceral Epithelial Cells, Glomerular,Epithelial Cells, Glomerular Visceral,Glomerular Visceral Epithelial Cells,Podocyte
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D058847 Inflammasomes Multiprotein complexes that mediate the activation of CASPASE-1. Dysregulation of inflammasomes has also been linked to a number of autoinflammatory and autoimmune disorders. Inflammasome,Pyroptosome,Pyroptosomes

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