title: NLRP3 inflammasome activation contributes to aldosterone-induced podocyte injury.
abstract: Aldosterone (Aldo) has been shown as an important contributor of podocyte injury. However, the underlying molecular mechanisms are still elusive. Recently, the pathogenic role of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in mediating renal tubular damage was identified while its role in podocyte injury still needs evidence. Thus the present study was undertaken to investigate the role of NLRP3 inflammasome in Aldo-induced podocyte damage. In vitro, exposure of podocytes to Aldo enhanced NLRP3, caspase-1, and IL-18 expressions in dose- and time-dependent manners, indicating an activation of NLRP3 inflammasome, which was significantly blocked by the mineralocorticoid receptor antagonist eplerenone or the antioxidantN-acetylcysteine. Silencing NLRP3 by a siRNA approach strikingly attenuated Aldo-induced podocyte apoptosis and nephrin protein downregulation in line with the blockade of caspase-1 and IL-18. In vivo, sinceday 5of Aldo infusion, NLRP3 inflammasome activation and podocyte injury evidenced by nephrin reduction occurred concurrently. More importantly, immunofluorescence analysis showed a significant induction of NLRP3 in podocytes of glomeruli following Aldo infusion. In the mice with NLRP3 gene deletion, Aldo-induced downregulation of nephrin and podocin, podocyte foot processes, and albuminuria was remarkably improved, indicating an amelioration of podocyte injury. Finally, we observed a striking induction of NLRP3 in glomeruli and renal tubules in line with an enhanced urinary IL-18 output in nephrotic syndrome patients with minimal change disease or focal segmental glomerular sclerosis. Together, these results demonstrated an important role of NLRP3 inflammasome in mediating the podocyte injury induced by Aldo.
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and.
authors.forename: Mi
authors.initials: M
authors.lastname: Bai
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York.
authors.forename: John Ci-Jiang
authors.initials: JC
authors.lastname: He
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and.
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China; jiazj72@hotmail.com.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and.
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.|Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000378:metabolism; D000450:Aldosterone / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology; D020382:Interleukin-18 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009404:Nephrotic Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D050199:Podocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C407223:NPHS2 protein; C492716:Nlrp3 protein, mouse; D018161:Receptors, Mineralocorticoid; C113267:nephrin; D000450:Aldosterone; D020170:Caspase 1
keywords: NOD-like receptor family, pyrin domain containing 3; inflammasome; inflammation