Shao Ying, He Ming, Zhou Li, Yao Tai, Huang Yu, Lu Li-min
Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Acta Pharmacol Sin. 2008 Jul;29(7):829-37. doi: 10.1111/j.1745-7254.2008.00812.x.
The renin-angiotensin system (RAS) plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. In the past few years, angiotensin (Ang) (1-7) has been reported to counteract the effects of Ang II and was even considered as a new therapeutical target in RAS. The present study aimed to investigate the effect of Ang (1-7) administration on a diabetic animal model and the modulation on local RAS.
Streptozotocin (STZ) injection-induced diabetic rats were used in the experiment. The animals were divided into 3 groups: (1) control; (2) STZ-induced diabetes; and (3) STZ-induced diabetes with chronic Ang (1-7) treatment [D+Ang(1-7)]. In the D+Ang(1-7) group, a dose of 25 microg x kg(-1) x h(-1) of Ang (1-7) was continually injected through the jugular vein by embedding miniosmotic pump for 6 weeks. Plasma glucose, ratio of kidney to body weight, and 24 h urine protein and serum creatinine were monitored by conventional measurement. Plasma and renal Ang II levels were measured by radioimmunoassay. Ang-converting enzyme (ACE), ACE2, Ang II type 1 (AT1) receptor, Ang II type 2 (AT2) receptor, Ang (1-7) Mas receptor, and TGF- beta1 mRNA levels were measured by real time PCR; ACE, ACE2, and TGF- beta1 protein levels were analyzed by Western blotting.
The renal function of diabetic rats was significantly retrogressed when compared with that of control rats. After the treatment by constant Ang (1-7) vein injection for 6 weeks, renal function was found to be even worse than diabetic rats, and both TGF-beta1 mRNA and protein levels were elevated in the D+Ang(1-7) group compared with the diabetic rats. The real-time PCR result also showed an increase in ACE mRNA expression and decrease in ACE2 mRNA level in the D+Ang(1-7) group when compared with diabetic rats. The number of AT1 receptors increased in the Ang (1-7)-injected group, while the number of AT2 and Mas receptors decreased.
Exogenous Ang (1-7) injection did not ameliorate STZinduced diabetic rat renal injury; on the contrary, it accelerated the progressive diabetic nephropathies.
肾素-血管紧张素系统（RAS）在血压控制以及体液和电解质稳态中起关键作用。在过去几年中，有报道称血管紧张素（Ang）（1-7）可抵消Ang II的作用，甚至被视为RAS中的一个新治疗靶点。本研究旨在探讨给予Ang（1-7）对糖尿病动物模型的影响以及对局部RAS的调节作用。
实验采用链脲佐菌素（STZ）注射诱导的糖尿病大鼠。动物被分为3组：（1）对照组；（2）STZ诱导的糖尿病组；（3）STZ诱导的糖尿病并接受慢性Ang（1-7）治疗组[D+Ang(1-7)]。在D+Ang(1-7)组中，通过植入微型渗透泵经颈静脉持续注射剂量为25μg·kg⁻¹·h⁻¹的Ang（1-7），持续6周。通过常规测量监测血糖、肾重与体重比、24小时尿蛋白和血清肌酐。采用放射免疫分析法测定血浆和肾组织中的Ang II水平。通过实时PCR检测血管紧张素转换酶（ACE）、ACE2、Ang II 1型（AT1）受体、Ang II 2型（AT2）受体、Ang（1-7）Mas受体及转化生长因子-β1（TGF-β1）的mRNA水平；通过蛋白质印迹法分析ACE、ACE2和TGF-β1的蛋白水平。
与对照组大鼠相比，糖尿病大鼠的肾功能显著减退。在持续静脉注射Ang（1-7）6周后，发现肾功能甚至比糖尿病大鼠更差，与糖尿病大鼠相比，D+Ang(1-7)组中TGF-β1的mRNA和蛋白水平均升高。实时PCR结果还显示，与糖尿病大鼠相比，D+Ang(1-7)组中ACE的mRNA表达增加，ACE2的mRNA水平降低。注射Ang（1-7）组中AT1受体数量增加，而AT2和Mas受体数量减少。
外源性注射Ang（1-7）并未改善STZ诱导的糖尿病大鼠肾损伤；相反，它加速了糖尿病肾病的进展。
