The Role of the (Pro)renin Receptor in Hypertensive Disease
The Role of the (Pro)renin Receptor in Hypertensive Disease
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DOI：
10.1093/ajh/hpv045
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发表时间：
2015-10-01
影响因子：
3.2
通讯作者：
Danser, A. H. Jan
中科院分区：
文献类型：
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作者：
Danser, A. H. Jan
组织血管紧张素的产生取决于循环（肾源性）肾素和/或其前体肾素原（统称为（原）肾素）的摄取。由于组织中的肾素水平通常高于基于组织中（含肾素）血液量的预期，因此提出了主动摄取机制。2002年发现的（原）肾素受体（（P）RR）似乎是一个有前途的候选者，尽管其对肾素/原肾素的纳摩尔亲和力比血液中的水平高出许多数量级。本文综述了（P）RR自发现以来的相关研究。首先，令人鼓舞的体外研究结果支持（原）肾素-（P）RR相互作用的有害作用，甚至导致血管紧张素非依赖性信号传导。此外，推定的（P）RR阻滞剂“手柄区肽”（HRP）在各种心血管动物模型中产生了有益的效果。然后怀疑这种相互作用是否真的发生在体内，（P）RR缺失出乎意料地被证明是致命的。此外，HRP结果无法得到证实。最后，人们发现（P）RR实际上是液泡型H+-ATP酶的一个组成部分，H +-ATP酶是一种多亚基蛋白，几乎存在于每种细胞类型中，对囊泡运输、蛋白质降解和偶联运输至关重要。然而，在脱氧皮质酮醋酸盐（DOCA）-盐模型中，用推定的拮抗剂PRO20（对应于前肾素前片段的前20个氨基酸）在脑中选择性（P）RR阻断降低了血压，并且（P）RR基因单核苷酸多态性与高血压相关。这在多大程度上与（原）肾素有关仍然不确定。高血压（P）RR阻滞的概念，如果追求，需要严格的测试任何新设计的拮抗剂，并可能不会持有承诺，鉴于组织特异性（P）RR基因敲除动物的早期死亡。
Tissue angiotensin generation depends on the uptake of circulating (kidney-derived) renin and/or its precursor prorenin (together denoted as (pro) renin). Since tissue renin levels are usually higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. The (pro) renin receptor ((P) RR), discovered in 2002, appeared a promising candidate, although its nanomolar affinity for renin/prorenin is many orders of magnitude above their levels in blood. This review discusses (P) RR-related research since its discovery. First, encouraging in vitro findings supported detrimental effects of (pro) renin-(P) RR interaction, even resulting in angiotensin-independent signaling. Moreover, the putative (P) RR blocker "handle region peptide" (HRP) yielded beneficial effects in various cardiovascular animal models. Then doubt arose whether such interaction truly occurs in vivo, and (P) RR deletion unexpectedly turned out to be lethal. Moreover, HRP results could not be confirmed. Finally, it was discovered that the (P) RR actually is a component of vacuolar-type H+-ATPase, a multisubunit protein found in virtually every cell type which is essential for vesicle trafficking, protein degradation, and coupled transport. Nevertheless, selective (P) RR blockade in the brain with the putative antagonist PRO20 (corresponding with the first 20 amino acids of prorenin's prosegment) reduced blood pressure in the deoxy-corticosteroneacetate (DOCA)-salt model, and (P) RR gene single nucleotide polymorphisms associate with hypertension. To what degree this relates to (pro) renin remains uncertain. The concept of (P) RR blockade in hypertension, if pursued, requires rigorous testing of any newly designed antagonist, and may not hold promise given the early death of tissue-specific (P) RR knockout animals.