|
- 2015
Nrf2抵抗胰岛β细胞氧化损伤的作用机制
|
Abstract:
摘要 长期高血糖导致糖尿病患者的氧化应激,引起胰岛β细胞氧化损伤,但核转录因子Nrf2(NF-E2-related factor 2)抵抗胰岛β细胞氧化损伤的作用机制还不清楚.本研究用低浓度葡萄糖(LG, 5.6 mmol/L)、LG + H2O2和高浓度葡萄糖(HG, 27.6 mmol/L)分别处理小鼠胰岛NIT-1β细胞48 h,检测细胞内活性氧(ROS,reactive oxygen species)生成、胰岛素合成与分泌变化和Nrf2入核表达水平.研究发现,高糖诱导NIT-1β细胞的ROS生成,降低细胞合成与分泌胰岛素的水平,但Nrf2入核表达降低胰岛β细胞氧化应激.结果提示Nrf2入核表达可以抵抗高糖诱导的胰岛β细胞氧化损伤,改善细胞合成与分泌胰岛素的功能.
[1] | Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C:dependent activation of NAD (P) H oxidase in cultured vascular cells[J]. Diabetes, 2000, 49(11): 1 939-1 945. |
[2] | Schvartz D. Dysfunction of rat INS-1E pancreatic-cells induced by chronic high glucose stimuli[D]. Geneva:University of Geneva, 2012. |
[3] | Talchai C, Xuan S, Lin H V, et al. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure[J]. Cell, 2012, 150(6): 1 223-1 234. |
[4] | Mahadevan J, Parazzoli S, Oseid E, et al. Ebselen treatment prevents islet apoptosis, maintains intranuclear <em>Pdx-1 </em>and <em>MafA</em> levels, and preserves β-cell mass and function in ZDF rats[J]. Diabetes, 2013, 62(10): 3 582-3 588. |
[5] | Nishikawa T, Araki E. Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications[J]. Antioxidants & Redox Signaling, 2007, 9(3): 343-353. |
[6] | Ungvari Z, Bailey-Downs L, Gautam T, et al. Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2011, 300(4): H1 133-H1 140. |
[7] | Nguyen T, Nioi P, Pickett C B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress[J]. Journal of Biological Chemistry, 2009, 284(20): 13 291-13 295. |
[8] | Deng X, Rui W, Zhang F, et al. PM<sub>2. 5</sub> induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells[J]. Cell Biology and Toxicology, 2013, 29(3): 143-157. |
[9] | Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism[J]. Trends in Molecular Medicine, 2004, 10(11): 549-557. |
[10] | Piconi L, Quagliaro L, Assaloni R, et al. Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction[J]. Diabetes/Metabolism Research and Reviews, 2006, 22(3): 198-203. |
[11] | Hang Y, Stein R. MafA and MafB activity in pancreatic β cells[J]. Trends in Endocrinology & Metabolism, 2011, 22(9): 364-373. |
[12] | Xu G, Chen J, Jing G, et al. Thioredoxin-interacting protein regulates insulin transcription through microRNA-204[J]. Nature Medicine, 2013, 19(9): 1 141-1 146.</p> |
[13] | <p> Polonsky K S. The past 200 years in diabetes[J]. New England Journal of Medicine, 2012, 367(14):1 332-1 340. |
[14] | Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited[J]. Arteriosclerosis, Thrombosis, and Vascular Biology, 2004, 24(5): 816-823. |
[15] | Yagishita Y, Fukutomi T, Sugawara A, et al. Nrf2 protects pancreatic β-Cells from oxidative and nitrosative stress in diabetic model mice[J]. Diabetes, 2014, 63(2): 605-618. |
[16] | Li J, Johnson D, Calkins M, et al. Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells[J]. Toxicological Sciences, 2005, 83(2): 313-328. |
[17] | Ren D, Villeneuve N F, Jiang T, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism[J]. Proceedings of the National Academy of Sciences, 2011, 108(4): 1 433-1 438. |
[18] | Xue M, Qian Q, Adaikalakoteswari A, et al. Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease[J]. Diabetes, 2008, 57(10): 2 809-2 817. |
[19] | Harmon J S, Gleason C E, Tanaka Y, et al. In vivo prevention of hyperglycemia also prevents glucotoxic effects on PDX-1 and insulin gene expression[J]. Diabetes, 1999, 48(10): 1 995-2 000. |
[20] | Kitamura Y I, Kitamura T, Kruse J P, et al. FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction[J]. Cell Metabolism, 2005, 2(3): 153-163. |
[21] | Lin Y, Sun Z. Current views on type 2 diabetes[J]. Journal of Endocrinology, 2010, 204(1): 1-11. |
[22] | Shao S, Fang Z, Yu X, et al. Transcription factors involved in glucose-stimulated insulin secretion of pancreatic beta cells [J]. Biochemical and Biophysical Research Communications, 2009, 384(4): 401-404. |
[23] | Stumvoll M, Goldstein B J, van H T W. Type 2 diabetes: principles of pathogenesis and therapy[J]. The Lancet, 2005, 365(9 467): 1 333-1 346. |
[24] | Kaneto H, Katakami N, Matsuhisa M, et al. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis[J]. Mediators of Inflammation, 2010,453 892:1-11. |
[25] | Kensler T W, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway[J]. Annu Rev Pharmacol Toxicol, 2007, 47: 89-116. |
[26] | Morrison C D, Pistell P J, Ingram D K, et al. High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling[J]. Journal of Neurochemistry, 2010, 114(6): 1 581-1 589. |