The kallikrein-kinin system as a regulator of cardiovascular and renal function.
The kallikrein-kinin system as a regulator of cardiovascular and renal function.
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DOI：
10.1002/cphy.c100053
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发表时间：
2011-04
影响因子：
5.8
通讯作者：
Carretero OA
中科院分区：
文献类型：
--
作者：
Rhaleb NE;Yang XP;Carretero OA
自分泌、旁分泌、内分泌和神经内分泌激素系统有助于调节心血管和肾脏功能。这些系统之间平衡的任何变化都可能导致高血压和靶器官损伤，无论原因是遗传、环境还是两者的组合。内分泌和神经内分泌血管升压激素，如肾素-血管紧张素系统(RAS)、醛固酮和儿茶酚胺，在调节血压和高血压和靶器官损伤的发病机制中起重要作用。尽管激肽等血管降压剂的作用尚未明确，但越来越多的证据表明，它们不仅对血压和肾功能至关重要，还可能反对心血管系统的重构。在这里，我们将主要关注激动素，这是一种含有缓激肽氨基酸序列的寡肽。它们由被称为激肽原的前体通过组织(腺体)和血浆激肽释放酶等酶产生。激肽的某些作用是通过二十烷基类化合物、一氧化氮、内皮衍生超极化因子和/或组织型纤溶酶原激活物(†PA)等介导的。激肽有助于预防心肌缺血，在预适应以及血管紧张素转换酶(ACE)和血管紧张素1型受体阻滞剂(ARB)的心血管和肾脏保护作用中发挥重要作用。但激肽在高血压发病机制中的作用仍存在争议。一项对犹他州家庭的研究表明，显性激肽释放酶基因表现为尿激肽释放酶高排泄，与降低患高血压的风险有关。此外，研究人员还发现了一种限制片段长度多态性(RFLP)，它将在一种自发性高血压大鼠(SHR)中发现的激肽释放酶基因家族与在正常血压的Brown挪威大鼠中发现的同源基因区分开来，并在这些SHR和Brown挪威大鼠的重组近交子品系中区分这种RFLP与血压升高共分离。然而，激肽释放酶激肽系统(KKS)的一个或多个成分缺乏或慢性KKS阻断的人、大鼠和小鼠并不患有高血压。在肾脏，激肽对于适当调节乳头状血流量和水和钠的排泄是必不可少的。B2-KO小鼠似乎对盐的升压作用更敏感。激肽与血管紧张素转换酶抑制剂的急性降压作用有关，但与其慢性作用无关(盐诱导的高血压除外)。激肽似乎在关节炎和皮肤炎症等炎症性疾病的发病机制中发挥作用；它们通过促进树突状细胞的成熟来作用于先天免疫，作为炎症的媒介，树突状细胞激活人体的适应性免疫系统，从而刺激促进炎症的机制。另一方面，通过NO作用的激肽有助于血管紧张素转换酶抑制剂在新生内膜形成过程中的血管保护作用。在缺血/再灌流引起的心肌梗死中，激肽在预适应或ACE抑制剂治疗后有助于缩小梗死范围。在继发于梗塞的心力衰竭中，血管紧张素转换酶抑制剂的治疗作用部分是通过释放NO的激动素介导的，而激活血管紧张素2型受体的药物部分是通过激动素和一氧化氮发挥作用的。因此，激肽在调节心血管和肾功能以及ACE抑制剂和ARB对高血压靶器官损害的许多有益作用中发挥着重要作用。
Autocrine, paracrine, endocrine, and neuroendocrine hormonal systems help regulate cardiovascular and renal function. Any change in the balance among these systems may result in hypertension and target organ damage, whether the cause is genetic, environmental or a combination of the two. Endocrine and neuroendocrine vasopressor hormones such as the renin-angiotensin system (RAS), aldosterone, and catecholamines are important for regulation of blood pressure and pathogenesis of hypertension and target organ damage. While the role of vasodepressor autacoids such as kinins is not as well defined, there is increasing evidence that they are not only critical to blood pressure and renal function but may also oppose remodeling of the cardiovascular system. Here we will primarily be concerned with kinins, which are oligopeptides containing the aminoacid sequence of bradykinin. They are generated from precursors known as kininogens by enzymes such as tissue (glandular) and plasma kallikrein. Some of the effects of kinins are mediated via autacoids such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and/or tissue plasminogen activator (†PA). Kinins help protect against cardiac ischemia and play an important part in preconditioning as well as the cardiovascular and renal protective effects of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARB). But the role of kinins in the pathogenesis of hypertension remains controversial. A study of Utah families revealed that a dominant kallikrein gene expressed as high urinary kallikrein excretion was associated with a decreased risk of essential hypertension. Moreover, researchers have identified a restriction fragment length polymorphism (RFLP) that distinguishes the kallikrein gene family found in one strain of spontaneously hypertensive rats (SHR) from a homologous gene in normotensive Brown Norway rats, and in recombinant inbred substrains derived from these SHR and Brown Norway rats this RFLP cosegregated with an increase in blood pressure. However, humans, rats and mice with a deficiency in one or more components of the kallikrein-kinin-system (KKS) or chronic KKS blockade do not have hypertension. In the kidney, kinins are essential for proper regulation of papillary blood flow and water and sodium excretion. B2-KO mice appear to be more sensitive to the hypertensinogenic effect of salt. Kinins are involved in the acute antihypertensive effects of ACE inhibitors but not their chronic effects (save for mineralocorticoidsalt-induced hypertension). Kinins appear to play a role in the pathogenesis of inflammatory diseases such as arthritis and skin inflammation; they act on innate immunity as mediators of inflammation by promoting maturation of dendritic cells, which activate the body’s adaptive immune system and thereby stimulate mechanisms that promote inflammation. On the other hand, kinins acting via NO contribute to the vascular protective effect of ACE inhibitors during neointima formation. In myocardial infarction produced by ischemia/reperfusion, kinins help reduce infarct size following preconditioning or treatment with ACE inhibitors. In heart failure secondary to infarction, the therapeutic effects of ACE inhibitors are partially mediated by kinins via release of NO, while drugs that activate the angiotensin type 2 receptor act in part via kinins and NO. Thus kinins play an important role in regulation of cardiovascular and renal function as well as many of the beneficial effects of ACE inhibitors and ARBs on target organ damage in hypertension.