[1]麦雨欣,王罗梓怡,余鹏,等.TO90可通过ACE2/Ang-(1-7)/MAS受体轴减轻Ang Ⅱ诱导人视网膜色素上皮细胞产生的炎症反应[J].第三军医大学学报,2019,41(20):1932-1938.
 MAI Yuxin,WANG Luoziyi,YU Peng,et al.TO90 inhibits angiotensin II-induced inflammatory response by up-regulating ACE2/Ang-(1-7)/MAS receptor axis in human retinal pigment epithelial cells[J].J Third Mil Med Univ,2019,41(20):1932-1938.
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TO90可通过ACE2/Ang-(1-7)/MAS受体轴减轻Ang Ⅱ诱导人视网膜色素上皮细胞产生的炎症反应(/HTML )
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
41卷
期数:
2019年第20期
页码:
1932-1938
栏目:
基础医学
出版日期:
2019-10-30

文章信息/Info

Title:
TO90 inhibits angiotensin II-induced inflammatory response by up-regulating ACE2/Ang-(1-7)/MAS receptor axis in human retinal pigment epithelial cells
作者:
麦雨欣王罗梓怡余鹏刘彦尧雷博
重庆医科大学第一附属医院眼科,重庆市眼科重点实验室,重庆市眼科研究所;郑州大学人民医院,河南省人民医院,河南省立眼科研究所,河南眼科医院
Author(s):
MAI Yuxin WANG Luoziyi YU Peng LIU Yanyao LEI Bo

Department of Ophthalmology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, 400016, China; People’s Hospital of Zhengzhou University and Henan Provincial People’s Hospital, Henan Eye Institute, Zhengzhou, Henan Province, 450003, China

关键词:
TO90Ang Ⅱ炎症反应ACE2MAS受体
Keywords:
TO90 angiotensin II inflammatory reaction angiotensin-converting enzyme 2 MAS receptor
分类号:
R392.3;R392.7;R774.1
文献标志码:
A
摘要:

目的 探讨TO90与ACE2/Ang-(1-7)/MAS受体轴在血管紧张素Ⅱ(angiotensin Ⅱ, Ang Ⅱ)诱导的人视网膜色素上皮细胞(retinal pigment epithelium cells,ARPE-19)炎症反应中的关系。方法 体外培养ARPE-19细胞,首先将其分为空白对照组及Ang Ⅱ模型组(1 μmol/L Ang Ⅱ刺激细胞48 h), Real-time PCR与ELISA检测慢性低度炎症因子IL-6、IL-8、MCP-1的表达,判断是否成功建立炎症模型。随后将ARPE-19细胞分为Ang Ⅱ模型组与TO90+Ang Ⅱ治疗组,重复之前步骤检测慢性低度炎症因子IL-6、IL-8、MCP-1表达;Real-time PCR及Western blot检测ACE2及MAS受体表达,探究TO90在Ang Ⅱ炎症模型中的作用。最后将ARPE-19细胞分为Ang Ⅱ模型组、TO90+Ang Ⅱ治疗组、A779(MAS受体抑制剂)+TO90+Ang Ⅱ抑制剂组以及A779+Ang Ⅱ抑制剂对照组,Real-time PCR、ELISA及Western blot重复之前步骤检测慢性低度炎症因子IL-6、IL-8、MCP-1、ACE2及MAS受体的表达,进一步验证TO90在Ang Ⅱ炎症模型中的作用。结果 AngⅡ刺激ARPE-19细胞后,IL-6、IL-8及MCP-1在mRNA及蛋白水平表达升高(P<0.05),TO90预处理ARPE-19细胞能显著减少IL-6、IL-8及MCP-1在mRNA及蛋白水平的表达(P<0.05),同时升高ACE2及MAS受体表达水平(P<0.05)。A779抑制后,与TO90+Ang Ⅱ治疗组相比,IL-6、IL-8及MCP-1在mRNA及蛋白水平表达量均显著升高(P<0.05),ACE2及MAS受体表达水平降低(P<0.05)。结论 TO90通过ACE2/Ang-(1-7)/MAS受体轴减轻Ang Ⅱ诱导人视网膜色素上皮细胞产生的炎症反应

Abstract:

ObjectiveTo investigate whether TO90 inhibits angiotensin II (Ang Ⅱ)-induced inflammatory response by regulating the expressions of ACE2/Ang-(1-7)/MAS receptor axis in human retinal pigment epithelial cells. MethodsIn vitro cultured ARPE-19 cells were treated with Ang Ⅱ for 48 h, and the changes in the expressions of interleukin-6 (IL-6), IL-8 and monocyte chemoattractant protein-1 (MCP-1) were detected using real-time PCR and enzyme-linked immunosorbent assay (ELISA) to verify the establishment of the inflammatory cell model. The effect of TO90 on the inflammatory response of Ang Ⅱ-treated ARPE-19 cells was evaluated by detecting the expression of IL-6, IL-8, MCP-1,ACE2 and MAS receptor using real-time PCR and Western blotting. ARPE-19 cells treated with Ang Ⅱ, TO90+Ang Ⅱ, A779 (a MAS receptor inhibitor)+TO90+Ang Ⅱ, or A779+Ang Ⅱ were examined for expressions of IL-6, IL-8, MCP-1, ACE2 and MAS receptors to further explore the effect of TO90 on Ang Ⅱ-induced inflammation response. ResultsAng Ⅱ treatment resulted in significantly increased expressions of IL-6, IL-8 and MCP-1 at both the mRNA and protein levels in ARPE-19 cells (P<0.05), and these effects were obviously attenuated by pretreatment of the cells with TO90 (P<0.05), which also caused significantly increased expressions of ACE2 and MAS receptor in the cells (P<0.05). In ARPE-19 cells treated with TO90+Ang Ⅱ, inhibition of MAS receptor with A779 significantly enhanced the expression of IL-6, IL-8, MCP-1,while inhibited the expression of ACE2 and MAS receptor at both the mRNA and protein levels (P<0.05). ConclusionTO90 inhibits Ang II-induced inflammatory response by up-regulating the expressions of ACE2/Ang-(1-7)/MAS receptor axis in ARPE-19 cells.

参考文献/References:

[1]CHEN M, XU H P. Parainflammation, chronic inflammation, and age-related macular degeneration[J]. J Leukoc Biol, 2015, 98(5):  713-725. DOI: 10.1189/jlb.3RI0615-239R.
[2]MELETH A D, AGRN E, CHAN C C, et al. Serum inflammatory markers in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2005, 46(11):  4295-4301. DOI: 10.1167/iovs.04-1057.
[3]SAKURAI E, ANAND A, AMBATI B K, et al. Macrophage depletion inhibits experimental choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2003, 44(8):  3578-3585. DOI: 10.1167/iovs.03-0097.
[4]CASCELLA R, RAGAZZO M, STRAFELLA C, et al. Age-related macular degeneration:  insights into inflammatory genes[J]. J Ophthalmol, 2014, 2014:  1-9. DOI: 10.1155/2014/582842.
[5]CHAPPELL M C. Nonclassical renin-angiotensin system and renal function[J]. Compr Physiol, 2012, 2(4):  2733-2752. DOI: 10.1002/cphy. c120002.
[6]LEUNG P S. The peptide hormone angiotensin II:  its new functions in tissues and organs[J]. Curr Protein Pept Sci, 2004, 5(4):  267-273.
[7]XU P, SRIRAMULA S, LAZARTIGUES E. ACE2/ANG-(1-7)/Mas pathway in the brain:  the axis of good[J]. Am J Physiol Regul Integr Comp Physiol, 2011, 300(4):  R804-R817. DOI: 10.1152/ ajpregu.00222.2010.
[8]QIU Y G, TAO L F, ZHENG S J, et al. AAV8-mediated angiotensin-converting enzyme 2 gene delivery prevents experimental autoimmune uveitis by regulating MAPK, NF-κB and STAT3 pathways[J]. Sci Rep, 2016, 6:  31912. DOI: 10.1038/srep31912.
[9]FU X Y, LIN R, QIU Y G, et al. Overexpression of angiotensin-converting enzyme 2 ameliorates amyloid β-induced inflammatory response in human primary retinal pigment epithelium[J]. Invest Ophthalmol Vis Sci, 2017, 58(7):  3018-3028. DOI: 10.1167/iovs.17-21546.
[10]CALKIN A C, TONTONOZ P. Liver x receptor signaling pathways and atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2010, 30(8):  1513-1518. DOI: 10.1161/ATVBAHA. 109.191197.
[11]GUIDEZ F, IVINS S, ZHU J, et al. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia[J]. Blood, 1998, 91(8):  2634-2642.
[12]IMAYAMA I, ICHIKI T, PATTON D, et al. Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1[J]. Hypertension, 2008, 51(6):  1631-1636. DOI: 10.1161/ HYPERTENSIONAHA.107.106963.
[13]YANG H X, ZHENG S J, QIU Y G, et al. Activation of liver X receptor alleviates ocular inflammation in experimental autoimmune uveitis[J]. Invest Ophthalmol Vis Sci, 2014, 55(4):  2795-2804. DOI: 10.1167/iovs.13-13323.
[14]ZHENG S J, YANG H X, CHEN Z H, et al. Activation of liver X receptor protects inner retinal damage induced by N-methyl-D-aspartate[J]. Invest Ophthalmol Vis Sci, 2015, 56(2):  1168-1180. DOI: 10.1167/ iovs.14-15612.
[15]HAZRA S, RASHEED A, BHATWADEKAR A, et al. Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes[J]. Diabetes, 2012, 61(12):  3270-3279. DOI: 10.2337/db11- 1596.
[16]QIU Y G, TAO L F, LEI C Y, et al. Downregulating p22phox ameliorates inflammatory response in Angiotensin II-induced oxidative stress by regulating MAPK and NF-κB pathways in ARPE-19 cells[J]. Sci Rep, 2015, 5:  14362. DOI: 10.1038/srep14362.
[17]DAI B L, LEI C Y, LIN R, et al. Activation of liver X receptor α protects amyloid β1-40 induced inflammatory and senescent responses in human retinal pigment epithelial cells[J]. et al, 2017, 66(6):  523-534. DOI: 10.1007/s00011-017- 1036-4.
[18]SUZUKI Y, RUIZ-ORTEGA M, LORENZO O, et al. Inflammation and angiotensin II[J]. Int J Biochem Cell Biol, 2003, 35(6):  881-900. DOI: 10.1016/s1357-2725(02)00271-6.
[19]NAGAI N, OIKE Y, IZUMI-NAGAI K, et al. Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization[J]. Arterioscler Thromb Vasc Biol, 2006, 26(10):  2252-2259. DOI: 10.1161/01.ATV.0000240050.15321.fe.
[20]KIM J H, KIM J H, YU Y S, et al. Blockade of angiotensin II attenuates VEGF-mediated blood-retinal barrier breakdown in diabetic retinopathy[J]. J Cereb Blood Flow Metab, 2009, 29(3):  621-628. DOI: 10.1038/jcbfm.2008.154.
[21]TAO L F, QIU Y G, FU X Y, et al. Angiotensin-converting enzyme 2 activator diminazene aceturate prevents lipopolysaccharide-induced inflammation by inhibiting MAPK and NF-κB pathways in human retinal pigment epithelium[J]. J Neuroinflammation, 2016, 13:  35. DOI: 10.1186/ s12974-016-0489-7.
[22]LEI P, BAYSA A, NEBB H I, et al. Activation of Liver X receptors in the heart leads to accumulation of intracellular lipids and attenuation of ischemia-reperfusion injury[J]. Basic Res Cardiol, 2013, 108(1):  323. DOI: 10. 1007/s00395-012-0323-z.
[23]KURIHARA T, OZAWA Y, ISHIDA S, et al. Renin-Angiotensin system hyperactivation can induce inflammation and retinal neural dysfunction[J]. Int J Inflam, 2012, 2012:  581695. DOI: 10.1155/2012/581695.
[24]STRAIN W D, CHATURVEDI N. The renin-angiotensin-aldosterone system and the eye in diabetes[J]. J Renin Angiotensin Aldosterone Syst, 2002, 3(4):  243-246. DOI: 10.3317/jraas. 2002.045.
[25]PASSOS-SILVA D G, VERANO-BRAGA T, SANTOS R A. Angiotensin-(1-7):  beyond the cardio-renal actions[J]. Clin Sci, 2013, 124(7):  443-456. DOI: 10.1042/CS20120461.
[26]SIMES E SILVA A C, SILVEIRA K D, FERREIRA A J, et al. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis[J]. Br J Pharmacol, 2013, 169(3):  477-492. DOI: 10.1111/bph.12159.
 

更新日期/Last Update: 2019-10-25