title: Antroquinonol mitigates an accelerated and progressive IgA nephropathy model in mice by activating the Nrf2 pathway and inhibiting T cells and NLRP3 inflammasome.
abstract: High levels of reactive oxygen species (ROS), systemic T cell activation, and macrophage infiltration in the kidney are implicated in the acceleration and progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis. However, the pathogenic mechanism of IgAN is still little understood, and it remains a challenge to establish a specific therapeutic strategy for this type of glomerular disorder. Recently, we showed that antroquinonol (Antroq), a pure active compound from Antrodia camphorata mycelium, inhibits renal inflammation and reduces oxidative stress in a mouse model of renal fibrosis. But the anti-inflammatory and immune-regulatory effects of Antroq on the acceleration and progression of primary glomerular disorders have not been determined. In this study, we show that Antroq administration substantially impeded the development of severe renal lesions, such as intense glomerular proliferation, crescents, sclerosis, and periglomerular interstitial inflammation, in mice with induced accelerated and progressive IgAN (AcP-IgAN). Further mechanistic analysis in AcP-IgAN mice showed that, early in the developmental stage of the AcP-IgAN model, Antroq promoted the Nrf2 antioxidant pathway and inhibited the activation of T cells and NLRP3 inflammasome. Significantly improved proteinuria/renal function and histopathology in AcP-IgAN mice of an established stage supported potential therapeutic effects of Antroq on the disease. In addition, Antroq was shown to inhibit activation of NLRP3 inflammasome in vitro by an IgA immune complex (IC) partly involving a reduced ROS production in IgA-IC-primed macrophages, and this finding may be helpful in the understanding of the mode of action of Antroq in the treated AcP-IgAN mice.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Shun-Min
authors.initials: SM
authors.lastname: Yang
authors.affiliation: Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan, ROC. Electronic address: shukmanka@gmail.com.
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan, ROC.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Chuang
authors.affiliation: Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Feng-Ling
authors.initials: FL
authors.lastname: Yang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Institute for Drug Evaluation Platform, Development Center for Biotechnology, Taipei, Taiwan, ROC.
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Chang
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC. Electronic address: annchen31717@gmail.com.
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000097:blood; D005922:Glomerulonephritis, IGA / Q000188:drug therapy*; D007111:Immunity, Cellular / Q000187:drug effects; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000517:prevention & control; D013601:T-Lymphocytes / Q000187:drug effects*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495636:Nfe2l2 protein, mouse; C492716:Nlrp3 protein, mouse; D014451:Ubiquinone; C545357:antroquinonol
keywords: Accelerated and progressive IgA nephropathy; Antroquinonol; Free radicals; Macrophage; NLRP3 inflammasome; Nrf2; ROS; T cell