Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8286903 | Redox Biology | 2017 | 14 Pages |
Abstract
Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co-immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co-immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway.
Keywords
PKGeNOSBDLN-acetyl-l-cysteinevWFcGMPNACLC3CD313MASGCULK1VASPCAV1DefenestrationAMPK3-methyladenineAMP-activated protein kinaseLSECROSunc-51 like autophagy activating kinase 1Adenosine TriphosphateATPaldosteroneAutophagyOxidationTemTEMPOliver sinusoidal endothelial cellendothelial nitric oxide synthaseVon Willebrand factorVasodilator-stimulated phosphoproteinSEMcyclic guanosine monophosphateScanning electron microscopyTransmission electron microscopyNitric oxidemicrotubule-associated protein 1 light chain 3protein kinase Gbile duct ligationcaveolin 1Reactive oxygen speciesMineralocorticoid receptor
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Authors
Xiaoying Luo, Dan Wang Dan Wang, Xuan Luo, Xintao Zhu, Guozhen Wang, Zuowei Ning, Yang Li, Xiaoxin Ma, Renqiang Yang, Siyi Jin, Yun Huang, Ying Meng, Xu Li,