Danser A H Jan
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Am J Hypertens. 2015 Oct;28(10):1187-96. doi: 10.1093/ajh/hpv045. Epub 2015 Apr 18.
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 deoxycorticosteroneacetate (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.
组织血管紧张素的生成取决于循环中（肾脏来源的）肾素和/或其前体肾素原（统称为（前体）肾素）的摄取。由于组织肾素水平通常高于根据组织中（含肾素的）血液量所预期的水平，因此有人提出了一种主动摄取机制。2002年发现的（前体）肾素受体（(P)RR）似乎是一个有前景的候选者，尽管其对肾素/肾素原的纳摩尔亲和力比它们在血液中的水平高出许多个数量级。本文综述了自(P)RR发现以来的相关研究。首先，令人鼓舞的体外研究结果支持了（前体）肾素-(P)RR相互作用的有害影响，甚至导致了不依赖血管紧张素的信号传导。此外，假定的(P)RR阻滞剂“柄区肽”（HRP）在各种心血管动物模型中产生了有益效果。随后，人们开始怀疑这种相互作用在体内是否真的发生，并且(P)RR缺失出乎意料地被证明是致命的。此外，HRP的结果无法得到证实。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，这是一种几乎存在于每种细胞类型中的多亚基蛋白，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，用假定的拮抗剂PRO20（与肾素原前肽的前20个氨基酸相对应）对大脑进行选择性(P)RR阻断可降低血压，并且(P)RR基因单核苷酸多态性与高血压相关。这与（前体）肾素的关联程度仍不确定。如果要在高血压中采用(P)RR阻断的概念，则需要对任何新设计的拮抗剂进行严格测试，并且鉴于组织特异性(P)RR基因敲除动物的早期死亡，可能前景并不乐观。
