苯那普利、缬沙坦对自发性高血压大鼠肾脏血管紧张素转换酶2表达的影响

Effects of Benazepril and Valsartan on ACE2 Expression in Kidney of SHR

目的观察苯那普利与缬沙坦对自发性高血压大鼠(SHR)血浆血管紧张素Ⅱ(AngⅡ)和肾脏血管紧张素转换酶2(ACE2)表达水平的影响,探讨ACE2在高血压发病机制和药物治疗中的意义。方法12周龄雄性SHR28只,分为空白对照组(Sc)、苯那普利组(10mg/kg.d)(Sb)、小剂量缬沙坦组(10mg/kg.d)(Sl)、大剂量缬沙坦组(30mg/kg.d)(Sh),每组7只,7只雄性WKY大鼠为正常对照。药物治疗3月后,用放射免疫法测定血浆AngⅡ含量,RT-PCR法测定肾脏中ACE和ACE2mRNA的表达水平,免疫组化法比较肾脏中ACE2蛋白的表达。结果与WKY大鼠相比,SHR肾脏中ACE2mRNA及其蛋白的表达均明显降低,而ACEmRNA的表达和血浆AngⅡ水平则明显升高(P<0.05)。缬沙坦治疗后SHR血压显著下降而血浆AngⅡ水平则进一步升高,肾脏中ACE2的表达水平明显升高,且呈剂量依赖性(P<0.05)。苯那普利治疗对SHR血浆AngⅡ水平及肾脏ACE2的表达则无明显影响。结论SHR体内ACE和ACE2的表达失衡可能在高血压的发病机制中有重要意义。血管紧张素受体拮抗剂(ARB)可能通过升高SHR血浆AngⅡ的水平而增加肾脏中ACE2的表达,ACE2表达的增加可能是ARB抗高血压治疗的一个新药理机制。

Objective To investigate the effects of benazepril and valsartan on plasma Ang Ⅱ and ACE2 expression in kidney of spontaneously hypertensive rats（SHR） and the role of ACE2 in the pathogenesis of hypertension. Methods Four groups of 12-week-old male SHR were studied with 7 rats in each group： placebo control （Sc）, benazepril （ 10 mg/kg · d） （Sb）, low-dose valsartan （ 10 mg/kg ·d） （SI） and high-dose valsartan （30 mg/kg · d） （Sh）. 7 male normotensive WKY rats were served as normal control. Drug therapy was administered for 3 months. Plasma Ang Ⅱ was measured by RIA. ACE and ACE2 mRNA in kidney were determined by RT-PCR and the expression level of ACE2 protein in kidney was measured by immunohistochemistry. Results The expression level of ACE2 mRNA and protein in kidney of SHR was significantly lower than WKY rats, while the level of and ACE mRNA in kidney was significantly higher（P〈0.05）. Valsartan treatment obviously lowered the blood pressure of SHR and increased plasma AngⅡ. The expression level of ACE2 （mRNA and protein）in kidney was increased by valsartan in a dose-dependent manner （P〈0. 05）. However, benazepril had little effect on plasma Ang Ⅱ and ACE2 mRNA expression in kidney. Conclusion The imbalance between ACE and ACE2 may play an important role in the mechanism of hypertension in SHR. The facts that angiotensin receptor blocker （ARB） increases plasma Ang Ⅱ and tissue ACE2 expression may be speculated as novel pharmacological mechanism of the anti-hypertensive effect of ARB.