糜蛋白酶抑制剂保护糖尿病仓鼠肾功能的机制研究

doi:10.13418/j.issn.1001-165x.2016.06.013

中国临床解剖学杂志 ›› 2016, Vol. 34 ›› Issue (6): 661-667.doi: 10.13418/j.issn.1001-165x.2016.06.013

糜蛋白酶抑制剂保护糖尿病仓鼠肾功能的机制研究

张孟姝¹，　刘金磊²，　刘学政³，　周红丽⁴，　张荣明¹

锦州医科大学 1.附属第一医院烧伤整形美容外科，　2. 附属第一医院放射线科，　3.人体解剖学教研室，
4.附属第一医院肾内科，辽宁锦州 121000

收稿日期:2015-11-05 出版日期:2016-11-25 发布日期:2016-12-20
通讯作者: 张荣明，教授，硕士生导师，E-mail：zhangrm2015@ sina.com
作者简介:张孟姝（1982-），女，辽宁锦州人，硕士，主管护师，主要从事糖尿病并发症的研究，E-mail：zhangmengshu2015@sina.com
基金资助:
国家自然科学基金（31140072）；辽宁省科技厅计划项目（2011225015）；辽宁省自然科学基金（20102140）

Protective effect of chymase inhibitor on renal function in diabetic hamsters

ZHANG Meng-shu¹, LIU Jin-lei², LIU Xue-zheng³，ZHOU Hong-li⁴, ZHANG Rong-ming¹

1. Department of Burn and Plastic Surgery, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000; 2. Department of Radiology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000; 3. Deparment of Anatomy, Jinzhou Medical University, Jinzhou 121000; 4. Department of Nephrology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China

Received:2015-11-05 Online:2016-11-25 Published:2016-12-20

摘要/Abstract

摘要：

目的　观察糜蛋白酶抑制剂对糖尿病仓鼠肾脏的保护作用，进而探讨其保护肾脏损伤的机理。方法　链脲佐菌素腹腔注射法制备仓鼠糖尿病模型。通过分子生物学技术、免疫组织化学技术、免疫印记技术检测各组动物糜蛋白酶，RAS成分：ACE、肾素、ANG-I、ANG-II；氧化应激水平：8-OhdG，NOX-4，p22phox，以及TGF-β1的表达情况。结果　糜蛋白酶抑制剂抑制了糖尿病仓鼠肾内ANG-II升高，同时明显降低了8-OHdG 分泌水平。NOX-4和p22phox染色表明糖尿病组血管球和肾小管区域氧化产物显著增高，而糜蛋白酶抑制剂抑制氧化产物的升高(P<0.01)。Western blot 证实了糖尿病组血管球NOX-4和p22phox蛋白的水平较对照组高，糜蛋白酶抑制剂显著降低了其表达。血管球TGF-β1表达糖尿病组高于对照组，同样糜蛋白酶抑制剂治疗后大大降低了TGF-β1水平。结论　糜蛋白酶抑制剂能保护糖尿病仓鼠的肾功能，其机制是通过降低肾内ANG-II水平和氧化应激水平来保护糖尿病肾脏损伤。

关键词: 糜蛋白酶抑制剂, 肾, 氧化应激, 糖尿病仓鼠

Abstract:

Objective　To observe the protective effect of chymotrypsin inhibitors on diabetic hamster kidney, and to explore mechanism underlying the protection.　Methods　Diabetic hamsters was established by intraperitoneal injection of STZ. The animal chymotrypsin, RAS components: ACE, renin, ANG-I, ANG-II; oxidative stress levels: 8-OhdG, NOX-4, p22phox, and the expression of TGF-β1 were determined by molecular biologic techniques, immunohistochemistry, western blotting technique.　Results　Chymotrypsin inhibitors inhibited the increase of ANG-II in diabetic hamster kidney, but significantly reduced the level of 8-OHdG secretion. NOX-4 and p22phox staining indicated significantly increased products of oxidation products in diabetic glomerulus and tubules, which could be significantly inhibited by chymotrypsin inhibitors (P<0.01). Western blot confirmed that the level of NOX-4 and p22phox increased in the diabetic group than in the control group, and chymotrypsin inhibitor could significantly reduce its expression. Glomerular TGF-β1 expression in the diabetic group was higher than that in the control group, and the chymotrypsin inhibitor therapy could significantly reduce the levels of TGF-β1.　Conclusions　Chymotrypsin inhibitors can protect diabetic hamster kidney function, and the underlying mechanism is through reducing renal ANG-II levels and oxidative stress levels to protect diabetic kidney damage.

Key words: Chymase inhibitor, Oxidative stress, Kidney, Diabetic hamsters

张孟姝,刘金磊,刘学政,周红丽,张荣明. 糜蛋白酶抑制剂保护糖尿病仓鼠肾功能的机制研究[J]. 中国临床解剖学杂志, 2016, 34(6): 661-667.

ZHANG Meng-shu, LIU Jin-lei, LIU Xue-zheng，ZHOU Hong-li, ZHANG Rong-ming. Protective effect of chymase inhibitor on renal function in diabetic hamsters[J]. Chinese Journal Of Clinical Anatomy, 2016, 34(6): 661-667.

参考文献

[1] Burnier M, Zanchi A. Blockade of the renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes[J]. J Hypertens, 2006, 24(1): 11-25.
[2] Mahmoud F, Al-Ozairi E. Inflammatory cytokines and the risk of cardiovascular complications in type 2 diabetes[J]. Disease Markers, 2013, 35(4): 235-241.
[3] Lavrentyev EN, Estes AM, Malik KU. Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells[J]. Circ Res, 2007, 101(5): 455-464.
[4] Doggrell SA, Wanstall JC. Vascular chymase: pathophysiological role and therapeutic potential of inhibition[J]. Cardiovasc Res, 2004, 61(4): 653-662.
[5] Huang XR, ChenWY, Truong LD, et al. Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular diseas[J]. J Am Soc Nephrol, 2003, 14(7): 1738-1747.
[6] Cristovam PC, Arnoni CP, de Andrade MC, et al. ACE-dependent and chymase- dependent angiotensin II generation in normal and glucose- stimulated human mesangial cells[J]. Exp Biol Med, 2008, 233(8): 1035-1043.
[7] Lee EJ, Chen HY, Lee MY, et al. Cinnamophilin reduces oxidative damage and protects against transient focal cerebral ischemia in mice[J]. Free Radic Biol Med, 2005, 39(4): 495-510.
[8] Yoo TH, Li JJ, Kim JJ, et al. Activation of the renin-angiotensin system within podocytes in diabetes[J]. Kidney Int, 2007, 71(10): 1019-1027.
[9] Gumprecht J, Zychma M, Grzeszczak W, et al. Angiotensin I-converting enzyme and chymase gene polymorphisms - relationship to left ventricular mass in type 2 diabetes patients[J]. Med Sci Monit, 2002, 8(8): CR603-CR606.
[10]Rong JM, Ji HZ, Wu XW, et al. Increased expression of chymase in inflammatory polyps in elderly patients with functional bowel disorder[J]. Exp Ther Med, 2014, 7(2):371-374.
[11]Wang Y, Gu Y, Lewis DF, et al. Elevated plasma chymotrypsin-like protease (chymase) activity in women with preeclampsia[J]. Hypertens Pregnancy, 2010, 29(3): 253-261.
[12]D'Orléans-Juste P, Houde M, Rae GA, et al. Endothelin-1 (1-31): from chymase-dependent synthesis to cardiovascular pathologies[J]. Vascul Pharmacol, 2008, 49(2-3): 51-62.
[13]Miyazaki M, Takai S, Jin D, et al. Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models[J]. Pharmacol Ther, 2006, 112(3): 668-676.
[14]Gorin Y, Block K, Hernandez J, et al. Nox4 NAD(P)H oxidase mediates hypertrophy and ?bronectin expression in the diabetic kidney[J]. J Biol Chem, 2005, 280(47): 39616-39626.

[1]	次旦旺久, 洛桑多吉, 拉孜, 拉巴顿珠, 尼玛. 藏族成人肾动脉血管变异多层螺旋CT观测[J]. 中国临床解剖学杂志, 2023, 41(6): 680-683.
[2]	钟伟兴, 谌祖江, 李俊桦, 邝珊珊, 王宁, 张璇, 李义凯. 消炎止痛膏对脂多糖诱导的C2C12分化肌管影响[J]. 中国临床解剖学杂志, 2023, 41(6): 716-720.
[3]	曹瀛心, 迟晓晨, 包翠芬, 李婷钰, 刘霞. 人参皂苷Rg1通过TNF-α/TNFR1/RIPKs通路调控急性肾损伤致急性肺损伤的保护机制研究[J]. 中国临床解剖学杂志, 2023, 41(4): 409-415.
[4]	陈平, 魏雪梅, 谈丽丽. 莫诺苷调控miR-483-5p表达对高糖诱导的人视网膜血管内皮细胞氧化应激和凋亡影响[J]. 中国临床解剖学杂志, 2023, 41(4): 434-439.
[5]	于露, 罗杰斯, 任毅, 赵艳, 杨文强, 杨新霞, 杨菁. 肌肽通过激活Nrf2/ARE信号通路改善OGD/R诱导星形胶质细胞损伤[J]. 中国临床解剖学杂志, 2023, 41(3): 310-317.
[6]	方喜波, 张英杰, 王洪新. 黄芩苷对糖尿病大鼠血管损伤的保护作用及机制[J]. 中国临床解剖学杂志, 2023, 41(3): 324-329.
[7]	黄星翔, 钟超, 叶华, 徐春贻, 刘云飞, 蒋璐. 基于Nrf2通路探讨松脂醇二葡萄糖苷改善小鼠骨质疏松的机制研究[J]. 中国临床解剖学杂志, 2023, 41(2): 162-171.
[8]	李玉标, 任安利, 丁宁, 赵喆, 董小涵, 李志敏, 董鹏. 正常左侧肾旁后间隙的CT解剖学研究[J]. 中国临床解剖学杂志, 2022, 40(4): 414-417.
[9]	李锐, 许财元, 孙贺, 张义龙. 斜外侧腰椎间融合术治疗退行性腰椎管狭窄症疗效及对患者氧化应激指标影响[J]. 中国临床解剖学杂志, 2022, 40(4): 491-496.
[10]	李琛, 张英杰, 孙洋, 王洪新. 视黄酸通过TLR4/NF-κB通路对脂多糖诱导血管炎症与氧化应激的影响[J]. 中国临床解剖学杂志, 2022, 40(3): 303-308.
[11]	赵振威, 刘艳洁, 李东, 于千, 周卫东, 吴敬章. 硕通镜与输尿管软镜治疗上尿路结石合并脓肾对清石率、尿脓毒血症、T淋巴细胞亚群的影响[J]. 中国临床解剖学杂志, 2022, 40(3): 347-355.
[12]	沈珈谊, 吕玲春, 陈俊, 赵雅楠, 卢陈英, 韦铁民. 浙西南地区中老年人群肾动脉影像解剖学特征[J]. 中国临床解剖学杂志, 2021, 39(5): 546-551.
[13]	马大亮, 崔红莉, 荣卫江, 贾琦, 黄福献. 柴胡皂苷A减轻脑缺血再灌注大鼠海马神经元损伤[J]. 中国临床解剖学杂志, 2021, 39(5): 569-574.
[14]	张丹妮, 王洪新. 肌肽对高糖诱导的大鼠H9C2心肌细胞损伤的保护作用及其机制[J]. 中国临床解剖学杂志, 2021, 39(4): 437-442.
[15]	邓博, 徐庶钦, 王方舟, 石宇航, 李益行, 吝怡, 樊茜, 吉琳, 陈雯雯, 吕毅, 严小鹏. 磁压榨技术治疗输尿管远端梗阻的实验研究[J]. 中国临床解剖学杂志, 2021, 39(3): 319-322.

糜蛋白酶抑制剂保护糖尿病仓鼠肾功能的机制研究

Protective effect of chymase inhibitor on renal function in diabetic hamsters

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

Metrics

本文评价

推荐阅读 0