A map and new directions for the (pro)renin receptor in the brain: focus on "A role of the (pro)renin receptor in neuronal cell differentiation".
A map and new directions for the (pro)renin receptor in the brain: focus on "A role of the (pro)renin receptor in neuronal cell differentiation".
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大脑中肾素（原）受体的图谱和新方向：重点关注“肾素（原）受体在神经元细胞分化中的作用”。
DOI：
10.1152/ajpregu.00287.2009
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
Lazartigues,Eric
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作者：
Lazartigues,Eric
（RAS）已经在外围和中枢神经系统（CNS）中发现了几个新成员，包括底物、酶和受体，人们可能会奇怪，为什么教科书仍然在教授这个系统过于简化和过时的版本。RAS远不是包含一个底物[血管紧张素原]，两个肽，[血管紧张素（ANG） I, ANG II]，两个酶[肾素，血管紧张素转换酶（ACE）]和一个受体（AT1）的直接级联，目前包括近十几个ANG片段，一些有活性，一些无活性，超过二十多个肽酶，至少六种不同的受体。此外，RAS现在由经典级联的上游和下游几个轴组成。虽然有时，这些新来者被认为是“缺失的环节”，但更多的时候，他们被怀疑。此外，目前人们普遍认为，局部ras存在于大多数器官和组织中，包括但不限于心脏、肾脏、脉管系统、脂肪组织、胰腺和大脑，它们参与这些组织的局部调节。自20世纪70年代初Ganten等人(3)首次对其进行描述以来，大脑RAS一直是争议和辩论的主题。ANG II是在大脑中产生的还是从周围传播的？angiii是中枢神经系统中AT1受体的真正配体吗？Mas是ANG的受体吗（1-7）？有非at1或非at2受体吗？angiv的结合位点是什么？虽然其中一些问题已经得到了解答，例如，现在人们普遍认为中枢神经系统中的ANG II可以在局部产生，也可以通过心室周围器官进入大脑，但其他说法仍然引发了争论。关于大脑RAS的最古老的争论可能与中枢神经系统中肾素的存在有关。由于肾素在大脑中的水平通常很低，而且可能在各个细胞核中不均匀，因此很难评估。因此，多年来出现了不同的理论，通常涉及ANG II合成的替代途径。因此，有证据表明，八肽可以通过tonin， chymase， cathepins和其他肽酶产生（见参考11的完整列表）。不依赖肾素合成ANG II的最新可能性之一涉及最近发现的ANG（1-12）肽（12），该肽最终可通过ACE的作用依次转化为ANG(1-10)，然后转化为ANG II。然而，正如Grobe等人最近回顾的那样(4)，遗传学研究反对肾素非依赖性途径，主要是因为在转基因动物中缺乏表型，在大脑中过度表达血管紧张素原，并支持该酶在中枢神经系统中的存在（1,7）。此外，有证据表明存在一种非分泌的细胞内形式的酶，肾素-b，它在啮齿动物和人类的大脑中起作用(5)。Genevieve Nguyen博士的团队在本期(2)中提出了一个新的难题。在这里，作者展示了（原）肾素受体[(P) RR]在中枢神经系统中的证据。(P) RR是由Nguyen组从X染色体(9)上发现(8)并克隆出来的。已知它可以结合肾素和“无活性”的前肾素，导致两种酶的活性增加，从而导致ANG I的形成增强（图1）。有趣的是，该受体的结合还会激活不依赖于ANG ii的细胞内信号通路，最终导致促纤维化基因的表达，如TGF-β、PAI-1等。虽然(P) RR的存在之前已经被这组研究人员在大脑(8)和其他研究人员在初级神经元（10）中发现，但这是第一次…
(RAS) has seen the discovery of several new members, both in the periphery and in the central nervous system (CNS), including substrates, enzymes, and receptors, and one may wonder why textbooks are still teaching an oversimplified and outdated version of this system. Far from being the straightforward cascade containing one substrate [angiotensinogen], two peptides,[angiotensin (ANG) I, ANG II], two enzymes [renin, angiotensin-converting enzyme (ACE)] and one receptor (AT1), the RAS currently includes nearly a dozen of ANG fragments, some active and some inactive, more than two dozen peptidases, and at least six different receptors. Moreover, the RAS now consists of several axes upstream and downstream of the classical cascade. While sometimes, these newcomers are considered to be “missing links,” more often they are viewed with skepticism. In addition, it is now well accepted that local RASs are present in most organs and tissues, including but not limited to the heart, kidney, vasculature, adipose tissue, pancreas, and brain, and they are involved in the local regulation of these tissues. Since its first description by Ganten et al.(3), in the early 1970s, the brain RAS has been the subject of controversy and debate. Is ANG II generated in the brain or does it travel from the periphery? Is ANG III the real ligand for the AT1 receptor in the CNS? Is Mas the receptor for ANG (1-7)? Is there a non-AT1, non-AT2 receptor? What is the binding site for ANG IV? Although some of these questions have been answered, for example, it is now well accepted that ANG II in the CNS can be generated locally, and it also can enter the brain via the circumventricular organs, other claims still spark debates. Probably the oldest controversy for the brain RAS concerns the presence of renin in the CNS. Because renin levels in the brain are usually low and likely not homogenous throughout the various nuclei, they have been difficult to assess. As a consequence, over the years, different theories have emerged, generally involving alternate pathways for the synthesis of ANG II. Accordingly, evidence has shown that the octapeptide could be produced via tonin, chymase, cathepsins, and other peptidases (see Ref. 11 for a full list). One of the latest possibilities for a renin-independent synthesis of ANG II involves the recently discovered ANG (1-12) peptide (12), which could eventually be transformed successively into ANG (1-10), then ANG II, through the action of ACE. However, as recently reviewed by Grobe et al.(4), genetic studies argue against renin-independent pathways, essentially because of the lack of phenotype in transgenic animals overexpressing angiotensinogen in the brain and support the presence of this enzyme in the CNS (1, 7). In addition, evidence has shown the existence of a nonsecreted intracellular form of the enzyme, renin-b, which is functional in the brain of rodents and humans (5). A new piece of the puzzle is presented in this issue (2) by Dr. Genevieve Nguyen’s group. Here, the authors show evidence of the (pro) renin receptor [(P) RR] in the CNS. The (P) RR was discovered (8) and cloned from the X chromosome (9) by the Nguyen group. It is known to bind both renin and the “inactive” prorenin, resulting in increased activity of both enzymes, thus leading to enhanced formation of ANG I (Fig. 1). Interestingly, binding of the receptor also leads to the activation of ANG II-independent intracellular signaling pathways, ultimately leading to the expression of profibrotic genes, such as TGF-β, PAI-1, and others.Although the presence of the (P) RR was previously identified by this group in the brain (8) and by others in primary neurons (10), this is the first …