坎地沙坦不同治疗时机对2型糖尿病KK/Ta小鼠肾脏血管紧张素1型和2型受体表达的影响

中国临床药理学与治疗学 ›› 2012, Vol. 17 ›› Issue (6): 627-633.

坎地沙坦不同治疗时机对2型糖尿病KK/Ta小鼠肾脏血管紧张素1型和2型受体表达的影响

范秋灵, 肇晓明, 蒲实, 李卅立, 杨刚, 姜奕, 王力宁

中国医科大学附属第一医院肾内科,沈阳 110001,辽宁

收稿日期:2011-12-23 修回日期:2012-03-28 出版日期:2012-06-26 发布日期:2012-06-25
通讯作者: 王力宁,女,硕士,教授,博士生导师,主要研究方向为糖尿病肾病和狼疮性肾炎发病机制的研究。Tel: 024-83282507 E-mail: lnwang56@medmail.com.cn
作者简介:范秋灵,女,博士,副教授,博士生导师,主要研究方向为糖尿病肾病遗传易感基因和发病机制。Tel: 13904012680 E-mail: cmufql@163.com
基金资助:
国家自然科学基金资助项目(30700369);教育部留学回国人员科研启动基金资助项目(教外司留[2006]331号);辽宁省教育厅高校科研计划项目(L2010658);沈阳市科技计划项目(F11-264-1-38)

Effects of candesartan early or late treatment on angiotensinⅡtype 1 and type 2 receptor expression in type 2 diabetic KK/Ta mice kidney

FAN Qiu-ling, ZHAO Xiao-ming, PU Shi, LI Sa-li, YANG Gang, JIANG Yi, WANG Li-ning

Department of Nephrology, the First Hospital of China Medical University, Shenyang 110001, Liaoning, China

Received:2011-12-23 Revised:2012-03-28 Online:2012-06-26 Published:2012-06-25

摘要/Abstract

摘要： 目的: 探讨坎地沙坦治疗对自发性2型糖尿病KK/Ta小鼠肾脏血管紧张素1型受体(AT1)和2型受体(AT2)表达的影响。方法: KK/Ta小鼠随机分为:非治疗组;早期治疗组:自6周龄起经口予坎地沙坦(4 mg·kg^-1·d^-1)治疗;晚期治疗组:自12周龄起予坎地沙坦治疗,正常对照组采用BALB/c小鼠。测定尿白蛋白排泄率、血压和糖耐量,计算总肾小球面积(WGA)、肾小球丛面积(GTA),细胞外系膜基质面积(ECMA)和肾小球内细胞核数目(NIGCN)。免疫荧光和免疫组化染色检测肾脏中AT1和AT2的表达。结果: 8周龄KK/Ta小鼠尿白蛋白/尿肌酐比率显著增加[(427.49±89.37) mg/g vs. (9.54±3.25) mg/g,P<0.01],WGA、GTA、ECMA和NIGCN增多,肾小球内AT1的表达增加,AT2的表达减少。坎地沙坦治疗显著减少KK/Ta小鼠尿白蛋白/尿肌酐比率[早期治疗组(32.18±9.41) mg/g,晚期治疗组(53.20±7.26) mg/g,P<0.01],减轻肾脏病理损害,抑制AT1的表达,上调AT2的表达,早期治疗组和晚期治疗组的作用无显著性差异。结论: KK/Ta小鼠肾脏中AT1受体表达增加,AT2受体表达减少。坎地沙坦治疗能够抑制AT1受体、上调AT2受体的表达,发挥其减少白蛋白尿,减轻糖尿病肾病病理损害的肾脏保护作用。

关键词: 糖尿病肾病, 坎地沙坦, KK/Ta小鼠, 血管紧张素1型受体, 血管紧张素2型受体

Abstract: AIM: To investigate the effects of candesartan, an angiotensin II type 1 receptor blocker (ARB) on angiotensin II type 1 (AT1) and type 2 (AT2) receptor expression in type 2 diabetic KK/Ta mouse kidneys. METHODS: KK/Ta mice divided into three groups were treated with candesartan (4 mg·kg^-1·d^-1) or vehicle from 6 or 12 to 28 weeks of age. BALB/c mice(n=6) treated with vehicle were used as controls. Body weight, blood pressure, blood glucose,urinary microalbumin,urinary creatinine and serum creatinine were measured every four weeks.At 28 weeks, morphometric analysis including the whole glomerular area (WGA), glomerular tuft area (GTA), extracellular matrix area (ECMA) and intraglomerular cell nuclei number (NIGCN) was conducted, and renal expressions of AT1 and AT2 were evaluated by immunohistochemistry and immunofluorescence. RESULTS: KK/Ta mice developed higher body weight, blood glucose, and urinary microalbumin/creatinine ratio in KK/Ta mice at 28 weeks of age were significantly higher than that of BALB/c mice (427.49±89.37 mg/g vs. 9.54±3.25 mg/g,P<0.01). AT1 expression was upregulated, and AT2 expression was downregulated in KK/Ta kidneys with increased WGA, GTA, ECMA and NIGCN. Candesartan treatment has markedly reduced urinary microalbumin/ creatinine ratio (Early treatment group: 32.18±9.41 mg/g,Late treatment group: 53.20±7.26 mg/g,P<0.01). Treatment with candesartan inhibited AT1 expression and increased AT2 expression. Candesartan treatment reduced WGA, GTA, ECMA, NIGCN, and mean blood pressure. There were no significant differences between the two treatment groups (from 6 or 12 weeks). CONCLUSION: The results suggest that candesartan, an ARB, attenuated glomerular hypertrophy and mesangial matrix accumulation and subsequent albuminuria by down-regulating AT1 expression and up-regulating AT2 expression in type 2 diabetic KK/Ta mouse kidneys.

Key words: Diabetic nephropathy, Candesartan, KK/Ta mice, Angiotensin Ⅱ type 1 receptor, Angiotensin Ⅱ type 2 receptor

中图分类号:

R965.2

范秋灵, 肇晓明, 蒲实, 李卅立, 杨刚, 姜奕, 王力宁. 坎地沙坦不同治疗时机对2型糖尿病KK/Ta小鼠肾脏血管紧张素1型和2型受体表达的影响[J]. 中国临床药理学与治疗学, 2012, 17(6): 627-633.

FAN Qiu-ling, ZHAO Xiao-ming, PU Shi, LI Sa-li, YANG Gang, JIANG Yi, WANG Li-ning. Effects of candesartan early or late treatment on angiotensinⅡtype 1 and type 2 receptor expression in type 2 diabetic KK/Ta mice kidney[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(6): 627-633.

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