title: PPARβ/δ activation protects against corticosterone-induced ER stress in astrocytes by inhibiting the CpG hypermethylation of microRNA-181a.
abstract: Increasing evidence indicates that peroxisome proliferator-activated receptors (PPARs) play neuroprotective roles in various neurodegenerative disease models in vivo and in vitro. However, the underlying mechanisms remain unclear. Astrocyte proliferation is a key process in neural development and plays significant roles in the regeneration of neural tissue after a penetrating injury. Corticosterone can significantly reduce the expression of glial fibrillary acid protein (GFAP) in cultured rat hippocampal astrocytes in vitro, and induce astrocytic dysfunction. Our research found that corticosterone treatment resulted in astrocyte damage and reduced the expression of PPARβ/δ. GW0742, a selective and high-affinity PPARβ/δ agonist, attenuated the corticosterone-induced astrocyte damage, but also significantly reversed the increase in the expression of GRP78 and CHOP, the two predominant proteins in endoplasmic reticulum (ER) stress. Moreover, GW0742 decreased the levels of caspase-12 and cleaved caspase-3, thereby protecting astrocytes against corticosterone-induced astrocyte apoptosis. We then confirmed that GRP78 was a target gene of microRNA-181a and found that PPARβ/δ activation increased microRNA-181a levels. Finally, we demonstrated that PPARβ/δ activation by GW0742 noticeably inhibited the activities and expression of DNA methyltransferases, and reduced the corticosterone-induced CpG island hypermethylation of microRNA-181a1 in astrocytes. Therefore, the present study is the first to reveal that PPARβ/δ activation suppresses CpG island hypermethylation-associated silencing of microRNA-181a and thereby protects against ER stress-induced damage in astrocytes. Our findings suggest that PPARβ/δ activation in astrocytes might be a promising target for regulating ER stress-induced astrocytic injury.
authors: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China.
authors: Juan
authors: J
authors: Ji
authors: The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
authors: Xiao-Ning
authors: XN
authors: Zeng
authors: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China.
authors: Lu-Lu
authors: LL
authors: Cao
authors: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China.
authors: Ling
authors: L
authors: Zhang
authors: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China.
authors: Zhan
authors: Z
authors: Zhao
authors: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China.
authors: Dan-Dan
authors: DD
authors: Yang
authors: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu 211166, China. Electronic address: xiulans@njmu.edu.cn.
authors: Xiu-Lan
authors: XL
authors: Sun
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003345:Corticosterone / Q000633:toxicity; D018899:CpG Islands / Q000187:drug effects / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D008745:Methylation / Q000187:drug effects; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D003345:Corticosterone; D035683:MicroRNAs; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; C581717:MIRN181 microRNA, rat; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: ER stress; GRP78; Methylation; PPARβ/δ; miR181a