Effects of human prorenin in rats transgenic for human angiotensinogen revisited
Effects of human prorenin in rats transgenic for human angiotensinogen revisited
复制标题
重新审视人肾素原对人血管紧张素原转基因大鼠的影响
作者：
C. Mercure;G. Prescott;M. Lacombe;D. Silversides;T. Reudelhuber
据报道，在糖尿病微血管并发症出现之前，循环中的肾素原（肾素的前体）水平升高。尽管一些使用动物模型的研究试图解决与高血压和糖尿病相关的组织重塑和损伤之间的联系，但结果是矛盾的，并且原肾素可能导致这些病理学的机制仍然是一个争论的主题。为了直接测试这些病理中的作用，我们产生了转基因小鼠与选择性增加（13至66倍）循环天然或活性位点突变的前肾素。在表达天然前肾素的小鼠中，收缩压没有变化或增加（+25 mm Hg），而表达活性位点突变的前肾素的小鼠与对照动物相比，收缩压没有显着差异。在任何测试的转基因动物中，即使在高龄（18个月），心脏纤维化或肾小球硬化也没有增加。Captopril（一种血管紧张素转换酶抑制剂）迅速使高肾素原血症小鼠的血压正常化，而输注假定的肾素原受体拮抗剂（手柄区肽）则没有效果。这些结果表明，循环中的肾素原慢性升高的主要后果是血压升高，并不支持肾素原作为心脏纤维化或肾小球损伤的主要致病因子的作用。活性位点突变的前肾素缺乏作用和血管紧张素转化酶抑制的功效也与前肾素通过生成血管紧张素II升高血压的作用一致。
Elevated levels of circulating prorenin, the precursor of renin, have been reported to precede the appearance of microvascular complications in diabetes mellitus. Although several studies using animal models have attempted to address the link between elevated prorenin and the tissue remodeling and damage associated with both hypertension and diabetes mellitus, the results have been contradictory, and the mechanism whereby prorenin might contribute to these pathologies remains a subject of debate. To directly test the role of prorenin in these pathologies, we generated transgenic mice with selective increases (13- to 66-fold) in circulating native or active site-mutated prorenin. Systolic blood pressure was either unchanged or increased (+25 mm Hg) in native prorenin-expressing mice, whereas the mice expressing active site-mutated prorenin showed no significant differences in systolic blood pressure compared with control animals. There was no increase in cardiac fibrosis or renal glomerular sclerosis in any of the transgenic animals tested, even at an advanced age (18 months). Captopril (an angiotensin-converting enzyme inhibitor) rapidly normalized blood pressure of hyperproreninemic mice, whereas infusion of the putative antagonist of the prorenin receptor (handle region peptide) had no effect. These results suggest that the primary consequence of chronic elevations in circulating prorenin is an increase in blood pressure and do not support a role for prorenin as the primary causative agent in cardiac fibrosis or renal glomerular injury. The lack of effect seen with active site-mutated prorenin and the efficacy of angiotensin-converting enzyme inhibition are also consistent with prorenin acting through the generation of angiotensin II to raise blood pressure.
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肾素原的非蛋白水解激活：肾素原受体的激活及其肾素原前段“诱饵肽”的抑制。
DOI：
10.2741/2716
发表时间：
2008
期刊：
Frontiers in bioscience : a journal and virtual library
影响因子：
--
作者：
Uddin,MNasir;Nabi,AHMNurun;Nakagawa,Tsutomu;Ichihara,Atsuhiro;Inagami,Tadashi;Suzuki,Fumiaki
通讯作者：
Suzuki,Fumiaki
影响因子：
13.6
作者：
Ichihara, Atsuhiro;Kaneshiro, Yuki;Inagami, Tadashi
通讯作者：
Inagami, Tadashi
影响因子：
13.6
作者：
Ichihara, Atsuhiro;Suzuki, Fumiaki;Inagami, Tadashi
通讯作者：
Inagami, Tadashi
影响因子：
158.5
作者：
LUETSCHER, JA;KRAEMER, FB;BRYERASH, M
通讯作者：
BRYERASH, M
影响因子：
19.6
作者：
Huang, Y;Wongamorntham, S;Border, W
通讯作者：
Border, W