ReviewThe interplay between Angiotensin II, TLR4 and hypertension
Graphical abstract
Introduction
Despite considerable advances in therapeutic management, the prevalence of hypertension and its contribution to death and disability continue to be a major public health challenge [1]. The etiology of hypertension is multifactorial, highly complex, and involves interplay between peripheral cardiovascular organs and the central nervous system (CNS). Among the various mechanisms contributing to the development of hypertension, it is well established that the dysregulation of Renin-Angiotensin System (RAS) plays a critical role in the generation and maintenance of the disease. Classically, RAS produces the active metabolite Angiotensin II (AngII) from angiotensinogen substrate primarily of hepatic origin [2]. Circulating AngII causes hypertension through direct actions in the kidney and blood vessels, and also by accessing the CNS. In addition to circulating AngII, tissue RAS, being able to produce AngII locally, has also been found in organs systems/organs such as the cardiovascular system, kidneys, and CNS, among others [3]. In the last few years, a large number of experimental studies have further demonstrated that local/tissue AngII is involved in key events of the inflammatory process, especially during hypertension. Indeed, the presence of immune components displaying a low-grade inflammation has been associated with hypertension. Several studies have discussed the contribution of adaptive immune responses involving different lymphocyte populations in various models of hypertension. However, the involvement of innate immunity, which is responsible for activation of adaptive response, mediating inflammation in hypertension, is still not well understood [4], [5], [6].
The innate immune system relies on pattern recognition receptors, of which, the family of Toll-like receptors (TLRs) has been most extensively studied. TLRs recognize a variety of pathogen-associated molecular patterns (PAMPs) and endogenous stress signals termed damage-associated molecular patterns (DAMPs) [7]. Activated intracellular domains of TLRs initiate a series of downstream signaling cascades through adaptor proteins, triggering an inflammatory response and subsequently interacting with the adaptive immune system for a more robust and specific response [8].
From the group of thirteen characterized TLRs, the most well-defined TLR involved in the etiology of hypertension is TLR4 [7], which will be the focus of this review. TLR4 induces inflammatory response by activation of two main pathways: 1) the myeloid differentiation primary-response protein 88 (MyD88)-dependent pathway, which involves the early phase of nuclear factor-κB (NF-κB) activation with consequent production of inflammatory cytokines; and 2) MyD88-independent pathways, which involves the late phase of NF-κB activation by activating interferon (IFN)-regulatory factor 3, leading to the production of IFN-β and the expression of IFN-inducible genes [8]. Early phase activation of NF-κB via MyD88-dependent pathway subsequently mediates the transcription of cyclooxygenase 2 (COX2) and pro-inflammatory cytokine genes [9]. COX2 is particularly important in the hypertension context because of its production of prostaglandins and subsequently thromboxane A2, a vasoconstrictor able to increase blood pressure [9].
Besides its classic role in the regulation of circulatory homeostasis, AngII acting mainly through Angiotensin type 1 receptor (AT1r) is acknowledged to act as a powerful pro-inflammatory mediator [10].
An association between AngII, inflammation, and increase in blood pressure, appears to play an important role in the kidney, vascular, and CNS alterations linked to hypertension. AngII inflammatory effects are mediated, in part, by activation of nuclear factor kappa-B (NF-κB), and the production of inflammatory mediators, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF). In that context, it has been shown that AT1r antagonist treatment reduced vascular expression of NF-κB in Spontaneously Hypertensive Rats (SHR), associated with reduction of IL-1β, and IL-6 [11]. An association between AngII and IL-6 mediating renal vasoconstriction [12] and chronic kidney disease [13] in experimental AngII-induced hypertension; as well as a role for IL-6 in AngII-mediated hypertension in human subjects has also been supported [14]. Within the CNS, central blockade of NF-κB decreases pro-inflammatory cytokines attenuating hypothalamic sympathoexcitation of AngII-induced hypertension [15]. Likewise, AngII-dependent hypertension is prevented by chronic blockade of TNF within the brain [16].
AngII, via AT1r, also stimulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox enzymes) and generates reactive oxygen species (ROS) [17]. Redox signaling within the vascular, kidney, and neuronal systems are implicated with hypertension. ROS contributes to endothelial dysfunction by inactivating nitric oxide [18], and to vascular inflammation by stimulating NF-κB, and upregulation of cytokines [19]. In AngII-dependent chronic hypertension, ROS, via Nox1, is associated with renal damage [20]. Within the CNS, ROS is associated with increases in neuronal activity and sympathetic outflow [21], [22], alongside with its influence in peripheral organs during hypertension [23].
As briefly discussed above, there is a consensus that inflammatory processes induced by AngII dysregulation, accompanied by the release of pro-inflammatory cytokines, and ROS, contributes to altered mean arterial blood pressure. Thus, suggesting that hypertension induced by AngII inflammatory signaling is associated with the activation of the immune system. There are excellent recent reviews in the literature covering the role of both adaptive and innate immune responses in hypertension [4], [6], [24], [25]. Our intent is concentrate our focus on AngII inflammatory actions involving the innate immune system via TLRs.
Recent studies have shown upregulation of TLR4 in the generation and maintenance of hypertension dependent on AngII. In this review, we aim to discuss the contribution of the innate immune system through the interactions of TLR4 and AngII within the kidney, vasculature, and CNS during hypertension.
Section snippets
AngII and TLR4 in hypertension: the kidneys
As the major biologically active hormone generated by the RAS system, AngII has powerful effects in controlling blood pressure and sodium homeostasis via the kidneys. In the renal system, AngII has a direct effect on the proximal tubules to increase sodium reabsorption and it has a complex and variable effect on glomerular filtration and renal blood flow depending on the setting [26]. Additionally, AngII acts on the adrenal cortex to stimulate the synthesis and secretion of aldosterone, a
Vascular inflammation, AngII, and TLR4 in hypertension
The RAS system plays a crucial role in the initiation and maintenance of vascular inflammation and the vascular remodeling characteristic of hypertension [48]. AngII mediates vasoconstriction, endothelial dysfunction, vascular remodeling, inflammation, and fibrosis, via multiple pathogenic mechanisms [49]. For example, it influences vascular permeability by increasing production of vascular endothelial growth factor. AngII also increases the expression of chemokines and cytokines, resulting in
Ang II, TLR4 and brain inflammation during hypertension
AngII plays a critical role in the regulation of cardiovascular function within the CNS. During normal conditions, AngII is a large hydrophilic peptide that normally does not cross the blood brain barrier (BBB). Circulating AngII is thought to gain access to the brain through neural areas devoid of BBB, namely the sensory circumventricular organs (CVOs) [59]. In the CVOs, AngII signaling influences cardiovascular control by activating key central pathways involved in blood pressure regulation
AngII-TLR4 crosstalk: signaling pathways
AngII has been found to increase oxidative stress and aggravate ROS production during hypertension by activating NADPH oxidases, subsequently stimulating multiple ROS-sensitive signaling cascades, and promoting release of inflammatory response factors, such as TNF-α, interleukins (IL)-1β, IL-6, and IL-12 [16], [103], [104]. In addition to this direct pro-inflammatory effect of RAS on its own, a putative indirect and/or modulatory role of AngII through crosstalk with TLR4 has been proposed
Final remarks
An association between the immune system and hypertension has long been recognized. The role of the adaptive immune system and lymphocytes has been well characterized. However, the contribution of the innate immune system in the etiology of hypertension, particularly via toll like receptors, is less understood. The activation or prime of the innate immune system ultimately leads the adaptive immune system to a more robust response; hence, it constitutes an important area of investigation.
A
Author Agreement/Declaration
All authors have seen and approved the final version of the manuscript being submitted.
Conflict of Interest
No conflicts exist.
Funding
This work was supported by the American Heart Association (grant number 14SDG20400015 to VCB and 12SDG12080023 to KPN).
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