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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.
AuthorsShun-Min Yang, Shuk-Man Ka, Kuo-Feng Hua, Tzu-Hua Wu, Yi-Ping Chuang, Ya-Wen Lin, Feng-Ling Yang, Shih-Hsiung Wu, Sung-Sen Yang, Shih-Hua Lin, Jia-Ming Chang, Ann Chen
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 61 Pg. 285-97 (Aug 2013) ISSN: 1873-4596 [Electronic] United States
PMID23567192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Carrier Proteins
  • Cytokines
  • Inflammasomes
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nfe2l2 protein, mouse
  • Nlrp3 protein, mouse
  • Ubiquinone
  • antroquinonol
Topics
  • Animals
  • Carrier Proteins (antagonists & inhibitors)
  • Cytokines (blood)
  • Glomerulonephritis, IGA (drug therapy)
  • Immunity, Cellular (drug effects)
  • Inflammasomes (antagonists & inhibitors)
  • Macrophages (drug effects, physiology)
  • Mice
  • NF-E2-Related Factor 2 (physiology)
  • NF-kappa B (antagonists & inhibitors)
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Oxidative Stress (drug effects)
  • Proteinuria (prevention & control)
  • T-Lymphocytes (drug effects)
  • Ubiquinone (analogs & derivatives, pharmacology, therapeutic use)

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