The Kallikrein‐Kinin System as a Regulator of Cardiovascular and Renal Function

Abstract

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 i...

Control of ENaC-Mediated Sodium Reabsorption in the Distal Nephron by Bradykinin

“…Multiple reports are consistent with the notion that renal KKS promotes diuresis and natriuresis largely due to inhibition of tubular reabsorption of water and sodium (de Souza et al, 2013;Mukai, Fitzgibbon, Bozeman, Margolius, & Ploth, 1996;Rhaleb, Yang, & Carretero, 2011;Siragy, 1993;Sivritas et al, 2008;Suzuki, Katori, Fujita, Kumagai, & Majima, 2000). It appears that these effects occur in the absence of changes in glomerular filtration rate and renal blood flow (Siragy, 1993;Sivritas et al, 2008).…”

“…It appears that these effects occur in the absence of changes in glomerular filtration rate and renal blood flow (Siragy, 1993;Sivritas et al, 2008). However, the evidence about a role of KKS in promoting vasodilation of renal vasculature also exists (Rhaleb et al, 2011). Taking into consideration the topology of renal KKS expression, it is suggested that inhibition of distal nephron water-electrolyte transport underlies the effects of kinins on renal function (Kauker & Nasjletti, 1986;Mukai et al, 1996;Zeidel, Jabs, Kikeri, & Silva, 1990).…”

Plasma Kallikrein-Kinin system mediates immune-mediated renal injury in trichloroethylene-sensitized mice

“…During activation of innate immunity, PK in local tissue plays a promoting role through activation of C3 (Oikonomopoulou et al 2013). Through binding to B2R, BK can induce maturation of dendrite cells (DC) and release of interleukin (IL)-12 (Rhaleb et al 2011). Kinin receptor profile may, thus, change in a variety of pathological conditions (Zelawski et al 2006).…”

“…All these provide compelling evidence for a significant role of the KKS in TCEinduced sensitization and associated kidney injury. In the past few decades, accumulating evidence has established that the KKS contributes to the pathogenesis of inflammation (Rhaleb et al 2011). However, its role in inflammation generated by environmental chemicals via sensitization was little studied.…”

Human Urinary kallidinogenase promotes good recovery in ischemic stroke patients with level 3 hypertension

“…In myocardial infarction produced by ischemia/reperfusion, kinins help reduce infarct size following preconditioning or treatment with angiotensin-converting enzyme (ACE) inhibitors (Rhaleb, Yang, & Carretero, 2011). Kinins act via nitric oxide (NO) contribute to the vascular protective effect of ACE inhibitors during neointima formation, and kallikrein/kinin leads to increased levels and Akt activation, and reduces reactive oxygen species formation, TGF-beta1 expression, MAPK, and nuclear factor-kappa B activation (Chao & Chao, 2005).…”