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Activation of the NLRP3 inflammasome in association with calcium oxalate crystal induced reactive oxygen species in kidneys.

ABSTRACT: We investigated the association of hyperoxaluria and calcium oxalate crystal induced production of reactive oxygen species with activation of the NLRP3 inflammasome.Eight-week-old male rats were given hydroxy-L-proline to induce hyperoxaluria. A group of rats on the hydroxy-L-proline diet also received apocynin, an antioxidant and nonspecific inhibitor of NADPH oxidase. At 28 days the rats were sacrificed and the kidneys were extracted. Microarray analysis was done with the BeadArray™ Reader. Gene ontology and gene pathway analyses were done with the DAVID (Database for Annotation, Visualization of Integrated Discovery) enrichment analysis tool. Quantitative real-time polymerase chain reaction and immunohistochemical staining were performed to confirm microarray results.Analysis of 22,226 genes revealed that 20 and 24 pathways were highly significant in the cortex and medulla, respectively. In the cortex extracellular matrix-receptor interaction, complement and coagulation cascades, focal adhesion and hypertrophic cardiomyopathy were the most significant pathways. In the medulla complement and coagulation cascades, extracellular matrix-receptor interaction and dilated cardiomyopathy were the major pathways. Genes encoding for PYCARD (ASC), TXNIP, NLRP3, caspase-1, and IL-1? and 18 were significantly up-regulated in hydroxy-L-proline fed rats but in the group that received apocynin these genes were down-regulated in the cortex and medulla. Results were verified by quantitative real-time polymerase chain reaction with SYBR® Green assay and immunohistochemical staining.Results indicate a role for reactive oxygen species in activation of the NLRP3 inflammasome via TXNIP. This led to a robust inflammatory response in the kidneys of rats with hyperoxaluria and calcium oxalate nephrolithiasis.

SUBMITTER: Joshi S

PROVIDER: S-EPMC4406847 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Activation of the NLRP3 inflammasome in association with calcium oxalate crystal induced reactive oxygen species in kidneys.

Joshi Sunil S Wang Wei W Peck Ammon B AB Khan Saeed R SR

The Journal of urology 20141128 5

<h4>Purpose</h4>We investigated the association of hyperoxaluria and calcium oxalate crystal induced production of reactive oxygen species with activation of the NLRP3 inflammasome.<h4>Materials and methods</h4>Eight-week-old male rats were given hydroxy-L-proline to induce hyperoxaluria. A group of rats on the hydroxy-L-proline diet also received apocynin, an antioxidant and nonspecific inhibitor of NADPH oxidase. At 28 days the rats were sacrificed and the kidneys were extracted. Microarray an ...[more]

PMID: 25437532

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Project description:AimsIncreased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation.ResultsRats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and pro-inflammatory cytokine secretion, janus-activated kinase 2/signal transducers and activators of transcription 3-mediated inflammatory signaling, and expression alteration of lipid metabolism-related genes in cultured hepatocytes and rat livers. NLRP3 silencing and caspase-1 suppression blocked these effects in primary rat hepatocytes and RHPCs, confirming that inflammasome activation alters hepatocyte lipid metabolism. Hepatocellular ROS and TXNIP were increased in animal and cell models. TXNIP silencing blocked NLRP3 inflammasome activation, inflammation, and lipid metabolism perturbations but not ROS induction in fructose-exposed hepatocytes, whereas antioxidants addition abrogated TXNIP induction and diminished the detrimental effects in fructose-exposed hepatocytes and rat livers.Innovation and conclusionsThis study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation. Antioxidant-based interventions can inhibit the ROS-TXNIP pathway.

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Activation of the NLRP3 inflammasome in association with calcium oxalate crystal induced reactive oxygen species in kidneys.

Publications

Activation of the NLRP3 inflammasome in association with calcium oxalate crystal induced reactive oxygen species in kidneys.

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