福辛普利对糖尿病视网膜病变小鼠血管紧张素转化酶2和血管内皮生长因子的影响

doi:10.16098/j.issn.0529-1356.2023.06.002

摘要/Abstract

摘要：

目的探讨福辛普利（Fos）对链脲佐菌素（STZ）诱导糖尿病视网膜病变（DR）小鼠的保护作用，及其对DR小鼠血管紧张素转化酶2（ACE2）和血管内皮生长因子（VEGF）表达的影响。方法 48只健康雄性昆明小鼠随机抽取36只，高脂饲料喂养6周后用SZT诱导制作糖尿病小鼠模型。模型制作成功后随机分为3组：模型组、Fos低浓度（5 mg/kg）组和Fos高浓度（10 mg/kg）组。12只小鼠为对照组。连续给药8周后，观察各组小鼠体质量和血糖变化，通过视网膜组织HE染色观察视网膜结构变化，采用ELISA法测定小鼠血清VEGF水平，运用免疫组织化学法观测小鼠视网膜组织ACE2的表达，Real-time PCR检测小鼠视网膜ACE2 mRNA表达，Western blotting检测小鼠视网膜ACE2和VEGF蛋白水平。结果 Fos（5 mg/kg 和10 mg/kg）能够显著减轻糖尿病小鼠视网膜内界膜层新生血管增生，下调糖尿病小鼠升高的血清中VEGF表达，促进糖尿病小鼠视网膜组织ACE2表达，Fos高浓度组作用效果较低浓度组好(P＜0.05)。结论福辛普利对糖尿病小鼠视网膜病变有保护作用，这种保护作用可能与上调ACE2的表达，降低VEGF表达有关。

关键词: 福辛普利, 糖尿病视网膜病变, 血管紧张素转化酶2, 血管内皮生长因子, 实时定量聚合酶链反应, 免疫印迹法, 小鼠

Abstract:

Objective To explore the protective effect of fosinopril (Fos) on streptozotocin (STZ) induced diabetic retinopathy(DR) mice and on the expression of angiotensin converting enzyme 2(ACE2) and vascular endothelial growth factor (VEGF) in DR mice. Methods Totally forty-eight healthy male Kunming mice, thirty-six were randomly selected，and a diabetic mouse model induced by STZ was constructed after 6 weeks of high-fat diet. After the successful establishment of the model, the thirty-six mice were randomly divided into three groups: model group, Fos low concentration (5 mg/kg) group, and Fos high concentration (10 mg/kg) group. The remaining twelve mice were served as the control group. After 8 weeks administration, the body weight and blood glucose level of mice in each group were determined. The change in the retinal structure was verified by HE staining. The serum level of VEGF was measured by ELISA. The expression of ACE2 in the retina tissue was verified by immunohistochemistry. The expression of ACE2 mRNA in diabetic retinopathy was analyzed by Real-time PCR. The levels of ACE2 and VEGF protein in diabetic retinopathy were detected by Western blotting. Results Fos (5 mg/kg, 10 mg/kg) reduced significantly the proliferation of neovascularization in the inner boundary layer, down-regulated the expression of VEGF in the serum of diabetic mice and promoted the expression of ACE2 in the retina tissue of diabetic mice. In addition, the effect of the high concentration group of Fos had a stronger effect than the lower concentration group(P＜0.05). Conclusion Fos has a protective effect on the retinopathy of diabetic mice. This protective effect may be mediated through the increased expression of ACE2 and the reduction of VEGF expression.

Key words: Fosinopril, Diabetic retinopathy, Angiotensin converting enzyme 2, Vascular endothelial growth factor, Real-time PCR, Western blotting, Mouse

中图分类号:

张琴杨俊霞蒋青松. 福辛普利对糖尿病视网膜病变小鼠血管紧张素转化酶2和血管内皮生长因子的影响[J]. 解剖学报, 2023, 54(6): 628-634.

ZHANG Qin YANG Jun-xia JIANG Qing-song. Effect of fosinopril on angiotensin converting enzyme 2 and vascular endothelial growth factor in diabetic retinopathy mice[J]. Acta Anatomica Sinica, 2023, 54(6): 628-634.

参考文献

［1］Wei H, Gu Q. SOX4 promotes high-glucose-induced inflammation and angiogenesis of retinal endothelial cells by activating NF-κB signaling pathway ［J］. Open Life Sci, 2022, 17(1): 393-400.

［2］Khademi F, Mohammadi Ｍ, Kiani A, et al. Efficient conjugation of aflatoxin M1 with bovine serum albumin through aflatoxin M1-(O-carboxymethyl) oxime and production of anti-aflatoxin M1 antibodies ［J］. Jundishapur J Microbiol, 2015, 8(4): e16850.

［3］Xue C, Zhou C, Yang B, et al. Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial［J］. BMJ Open, 2017, 7(2):1-8.

［4］Li ZG, Liu YQ, Zhang HJ, et al. Effect of fosinopril on the renal cortex protein expression profle of otsuka long-evans tokushima fatty rats ［J］. Exp Ther Med, 2020, 19(1): 172-182.

［5］Lin Y, Cui Y, Yuan Y, et al. Plasma fibroblast growth factor 23 as a predictor for fosinopril therapeutic efficacy in pediatric primary hypertension［J］. J Am Heart Assoc, 2022, 11(7): e023182.

［6］Zhu XCh, Li XL, Ma WF, et al. Effects of fosinopril on central retinal artery hemodynamics in diabetic patients［J］. Clinical Medicine of China, 2001, 17(7): 532-533. (in Chinese)

朱显成, 李秀兰, 马文璠, 等. 福辛普利对糖尿病患者视网膜中央动脉血流动力学的影响［J］. 中国综合临床, 2001, 17(7): 532-533.

［7］Ni J, Yang F, Huang XR, et al. Dual deficiency of angiotensin-converting enzyme-2 and Mas receptor enhances angiotensin Ⅱ-induced hypertension and hypertensive nephropathy［J］. J Cell Mol Med, 2020, 24(22): 13093-13103.

［8］Liu N, Cai KL. The protective effect of ACE2-Ang-(1-7)Mas axis on diabetic retinopathy［J］. Chinese Journal of Ophthalmologic Medicine, 2013, 2(3): 34-37.(in Chinese)

刘娜, 蔡可丽. ACE2-Ang-(1-7)-Mas轴对糖尿病视网膜病变的保护作用［J］. 中华眼科医学杂志, 2013, 2(3): 34-37.

［9］Dong ZhJ, Tao XY, Wang HB, et al. Effects of purendan superfine powder on expression of retinal vascular endothelial growth factor and pigment epithelium-derived factor in diabetic rats ［J］. Acta Anatomic Sinica, 2011, 42(4): 498-502.(in Chinese)

董志军,陶相宜,王海彬,等.菩人丹超微粉对糖尿病大鼠视网膜血管内皮生长因子和色素上皮衍生因子表达的影响［J］. 解剖学报, 2011, 42(4): 498-502.

［10］Hu Y, Xie A, Cheng Q. Upregulated CD200 in pre-retinal proliferative fibrovascular membranes of proliferative diabetic retinopathy patients and its correlation with vascular endothelial growth factor［J］. Inflamm Res, 2019, 68(12): 1071-1079.

［11］Arrigo A, Aragona E, Bandello F. VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy［J］. Ann Med, 2022, 54(1): 1089-1111.

［12］Kuang JS, Zhao YR, Zhao YY, et al. The studying of fosinopril combined with fenofibrate on the preventing of diabetic retinopathy in diabetic mice［J］. Tianjin Medical Journal, 2016, 44 (3): 322-326. (in Chinese)

旷劲松, 赵玉蓉, 赵玉岩, 等. 福辛普利联合非诺贝特对糖尿病小鼠视网膜病变干预作用的研究［J］. 天津医药, 2016, 44(3): 322-326.

［13］Zheng Z, Chen H, Xu X, et al. Effects of angiotensin-converting enzyme inhibitors and beta-adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathy［J］. Exp Eye Res, 2007, 84(4): 745-752.

［14］Chen F, Xiong H, Wang J, et al. Anti-diabetic effect of total flavonoids from Sanguis draxonis in type 2 diabetic rats［J］. J Ethnopharmacol, 2013, 149(3): 729-736.

［15］Oh JH, Kim SW, Kwon SS, et al. The change of macular thickness following single-session pattern scan laser panreti-nal photocoagulation for diabetic retinopathy［J］. Graefes Arch Clin Exp Ophthalmo, 2015, 253(1): 57-63.

［16］Huang H, Hu L, Lin J, et al. Effect of fosinopril on chemerin and VEGF expression in diabetic nephropathy rats ［J］. Int J Clin Exp Pathol, 2015, 8(9): 11470-11474.

［17］Sun P, Xu N, Li Y, et al. Destruction of the blood-retina barrier in diabetic retinopathy depends on angiotensin-converting enzyme-mediated TGF-β1/Smad signaling pathway activation［J］. Int Immunopharmacol, 2020, 85(7): 106686.

［18］Park K, Chen Y, Hu Y, et al. Nanoparticle-mediated expression of an angiogenic inhibitor ameliorates ischemia-induced retinal neovascularization and diabetes-induced retinal vascular leakage ［J］. Diabetes, 2009, 58(8): 1902-1913.

［19］Brownlee M. The pathobiology of diabetic complications: a unifying mechanism［J］. Diabetes, 2005, 54(6): 1615-1625.

［20］Guo ShP, Huang ShH, Dong Y, et al. The Amelioration of qingxiangzi (celosia argentea L) extract (CAE) on streptozotocin (STZ)-induced DR and its engaged mechanism［J］. Guiding Journal of Traditional Chinese Medicine and Pharmacy, 2016, 22(18): 27-30. (in Chinese)

郭树鹏, 黄世红, 董彦, 等. 青葙子提取物改善糖尿病视网膜病活性及其机理研究［J］. 中医药导报, 2016, 22(18): 27-30.

［21］Souza SRA, Oliveira SW, Alzamora AC, et al. The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7)［J］. Physiol Rev, 2018, 98(1): 505-553.

［22］Foureaux G, Nogueira BS, Coutinho DC, et al. Activation of endogenous angiotensin converting enzyme 2 prevents early injuries induced by hyperglycemia in rat retina［J］.Braz J Med Biol Res, 2015, 48(12): 1109-1114.

［23］Dominguez JM, Hu P, Caballero S, et al. Adeno-associated virus overexpression of angiotensin-converting enzyme-2 reverses diabetic retinopathy in type 1 diabetes in mice［J］. Am J Pathol, 2016, 186(6): 1688-1700.

［24］Duan Y, Beli E, Calzi SL, et al. Loss of angiotensin‐converting enzyme 2 exacerbates diabetic retinopathy by promoting bone marrow dysfunction［J］. Stem Cells, 2018, 36(9): 1430-1440.

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