Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors
Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors
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DOI：
10.1111/j.1523-1755.2005.00675.x
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发表时间：
2005-11-01
影响因子：
19.6
通讯作者：
Chappell, MC
中科院分区：
文献类型：
--
作者：
Ferrario, CM;Jessup, J;Chappell, MC
肾素-血管紧张素系统阻断对肾血管紧张素-(1-7)形成酶和受体的影响。研究了血管紧张素转换酶（ACE）2对ACE抑制剂不敏感，并高效地从血管紧张素II （Ang II）生成血管紧张素-(1-7)[Ang-(1-7)]对赖诺普利、氯沙坦及两种药物联合慢性阻断的反应。36只成年Lewis大鼠连续2周在饮水中服用这些药物，同时在整个研究过程中记录它们的动脉压、饮水量和尿量。肾脏排泄变量的测量包括评估血管紧张素I （Ang I）、Ang II和Ang-(1-7)的排泄率，而在研究完成时收集的血液用于测量血浆血管紧张素浓度。采用半定量逆转录酶（RT）实时聚合酶链式反应（PCR）检测肾皮质样品中肾素、血管紧张素原（Aogen）、尿激酶溶素、血管紧张素1型和2型(AT（1)和AT(2)）及mas受体mrna的含量。ACE2活性测定为Ang II转化为Ang-的速率（1-7）。在服用赖诺普利或氯沙坦的大鼠中获得了相当的血压降低，而这两种药物都产生了更大的动脉压降低。在所有三种治疗形式中，多尿记录与渗透压降低有关，但肌酐排泄没有变化。赖诺普利增加了血浆中Ang I和Ang-的水平和尿排泄率（1-7），而血浆中Ang II降低，但对尿中Ang II没有影响。氯沙坦对血浆和尿中Ang-产生类似的变化（1-7），但增加了血浆Ang II，但未改变尿中Ang II的排泄。联合治疗模拟了赖诺普利对血浆和尿液中Ang I和Ang-(1-7)水平的影响。给予赖诺普利或联合用药的大鼠肾皮质Aogen mRNA增加，而所有三种治疗均产生肾素mRNA的强劲增加。相比之下，ACE、ACE2、neprilysin、AT(1)和mas受体mrna在所有三种治疗中保持不变。赖诺普利和氯沙坦联合用药可显著增强大鼠肾皮质ACE2活性，而联合用药组无明显变化。我们的数据揭示了ACE2在正常血压大鼠肾脏中由Ang II生成Ang-(1-7)中的作用，这主要反映在给予赖诺普利或氯沙坦的大鼠肾膜中测量的ACE2活性增加。这些数据进一步表明，ACE抑制或AT(1)受体阻断后，动物尿液中Ang-(1-7)水平升高反映了肾内七肽的形成。
Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors.Background. Angiotensin-converting enzyme (ACE)2, a homologue of ACE, which is insensitive to ACE inhibitors and forms angiotensin-(1-7) [Ang-(1-7)] from angiotensin II (Ang II) with high efficiency was investigated in response to chronic blockade with lisinopril, losartan, and both drugs combined.Methods. Thirty-six adult Lewis rats were assigned to receive these medications in their drinking water for 2 weeks while their arterial pressure, water intake, and urine volume were recorded throughout the study. Measures of renal excretory variables included assessing excretion rates of angiotensin I (Ang I), Ang II and Ang-(1-7) while blood collected at the completion of the study was used for measures of plasma angiotensin concentrations. Samples from renal cortex were assayed for renin, angiotensinogen (Aogen), neprilysin, angiotensin types 1 and 2 (AT(1) and AT(2)) and mas receptor mRNAs by semiquantitative reverse transcriptase (RT) real-time polymerase chain reaction (PCR). ACE2 activity was determined as the rate of Ang II conversion into Ang-(1-7).Results. Comparable blood pressure reductions were obtained in rats medicated with either lisinopril or losartan, whereas both drugs produced a greater decrease in arterial pressure. Polyuria was recorded in all three forms of treatment associated with reduced osmolality but no changes in creatinine excretion. Lisinopril augmented plasma levels and urinary excretion rates of Ang I and Ang-(1-7), while plasma Ang II was reduced with no effect on urinary Ang II. Losartan produced similar changes in plasma and urinary Ang-(1-7) but increased plasma Ang II without changing urinary Ang II excretion. Combination therapy mimicked the effects obtained with lisinopril on plasma and urinary Ang I and Ang-(1-7) levels. Renal cortex Aogen mRNA increased in rats medicated with either lisinopril or the combination, whereas all three treatments produced a robust increase in renal renin mRNA. In contrast, ACE, ACE2, neprilysin, AT(1), and mas receptor mRNAs remained unchanged with all three treatments. Renal cortex ACE2 activity was significantly augmented in rats medicated with lisinopril or losartan but not changed in those given the combination.Conclusion. Our data revealed a role for ACE2 in Ang-(1-7) formation from Ang II in the kidney of normotensive rats as primarily reflected by the increased ACE2 activity measured in renal membranes from the kidney of rats given either lisinopril or losartan. The data further indicate that increased levels of Ang-(1-7) in the urine of animals after ACE inhibition or AT(1) receptor blockade reflect an intrarenal formation of the heptapeptide.