title: Mitochondrial reactive oxygen species-mediated NLRP3 inflammasome activation contributes to aldosterone-induced renal tubular cells injury.
abstract: Aldosterone (Aldo) is an independent risk factor for chronic kidney disease (CKD), and although Aldo directly induces renal tubular cell injury, the underlying mechanisms remain unclear. NLRP3 inflammasome and mitochondrial reactive oxygen species (ROS) have recently been implicated in various kinds of CKD. The present study hypothesized that mitochondrial ROS and NLRP3 inflammasome mediated Aldo-induced tubular cell injury. The NLRP3 inflammasome is induced by Aldo in a dose- and time-dependent manner, as evidenced by increased NLRP3, ASC, caspase-1, and downstream cytokines, such as interleukin (IL)-1β and IL-18. The activation of the NLRP3 inflammasome was significantly prevented by the selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL) (P < 0.01). Mice harboring genetic knock-out of NLRP3 (NLRP3(-/-)) showed decreased maturation of renal IL-1β and IL-18, reduced renal tubular apoptosis, and improved renal epithelial cell phenotypic alternation, and attenuated renal function in response to Aldo-infusion. In addition, mitochondrial ROS was also increased in Aldo-stimulated HK-2 cells, as assessed by MitoSOXTM red reagent. Mito-Tempo, the mitochondria-targeted antioxidant, significantly decreased HK-2 cell apoptosis, oxidative stress, and the activation of NLRP3 inflammasome. We conclude that Aldo induces renal tubular cell injury via MR dependent, mitochondrial ROS-mediated NLRP3 inflammasome activation.
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.affiliation: Division of Nephrology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Honglei
authors.initials: H
authors.lastname: Guo
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Chengyan
authors.initials: C
authors.lastname: Xu
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Huashan Hospital and Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
mesh_terms: D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D000450:Aldosterone
keywords: NLRP3 inflammasome; Pathology Section; aldosterone; chronic kidney disease; mitochondrial reactive oxygen species; renal tubular cells