A New Role for Angiotensin II in Aging
1. Introduction to angiotensin II
Control of fluid volume homeostasis is essential for life, and the complex systems dedicated to this task in humans are the result of evolutionary processes shaped by survival responses[4]. For example, in response to trauma, activation of the sympathetic nervous system promotes the release of renin, angiotensin, aldosterone, catecholamines and natriuretic peptides, which act to maintain fluid pressure in the circulation despite the loss of body fluids that can occur as a result of haemorrhage[22][72]. Maintenance of volume balance allows animals to migrate from salt in seawater to fresh water and dry land[59]. During human evolution, the renin-angiotensin system (RAS) played an important role in controlling salt intake and stimulating thirst.
Studies of contemporary primitive tribes have shown that hunter-gatherer ancestors survived on small amounts of salt, which may have benefited from activation of the renin-angiotensin system, without suffering from hypertension[33]. As dietary habits changed, salt intake increased, turning the RAS-mediated increase in blood pressure into a negative factor. Thus, natural selection has a major influence on the development of hypertension, and the prevalence of hypertension varies considerably between geographical and ethnic population [70]. Ancient humans living in hot and humid regions, such as the tropics, have evolved a tendency to retain salt as an adaptation to low salt availability and the risk of electrolyte imbalance[19]. In contrast, populations in cooler, drier climates, such as temperate zones, have adapted to conditions of higher sodium availability and lower sodium loss[19]. In this context, variation in the human RAS gene may be partly responsible for regional differences in susceptibility to hypertension[41]. In addition to salt retention and hypertension, recent studies have elucidated the role of the RAS, and in particular its major effector molecule angiotensin II (Ang II), in inflammation, autoimmunity and ageing. The aim of this review is to highlight these novel roles of angiotensin II and their potential clinical implications.
2. Effects of components of the renin-angiotensin system
In 1898, Robert Tigerstedt and his student Per Gunnar Bergman discovered the presence of a presser substance in rabbit kidney cortical extracts and named it renin[64].In 1934, Henry Goldblatt demonstrated that constricting the renal arteries of dogs with silver clips produced chronic hypertension[20]. Subsequently, using the same technique, Braun-Menendez et al. and Page and Helmer demonstrated renal secretion of angiotensin, another compound with a rapid presser effect of very short duration [7][6][45]. Our understanding of the physiology and pathophysiology of Ang II has improved considerably since these early studies.
2.1 Angiotensin peptides
Ang II is an octapeptide formed from the substrate angiotensinogen by the sequential enzymatic cleavage of renin and angiotensin converting enzyme (ACE). Specifically, renin cleaves angiotensinogen to form angiotensin I, which is converted to angiotensin II by angiotensin-converting enzyme. The substrate angiotensinogen is produced in the liver, renin in the kidneys and Ang II in vascular tissue[65].ACE is a circulating enzyme that also degrades bradykinin to inactive fragments, thereby reducing serum levels of endogenous vasodilators[8][17]. It is conceivable that the same may be true in patients with cardiovascular disease or progressive decline in brain function, including dementia and Alzheimer's disease, but such studies are lacking.
ACE2 is another carboxypeptidase that cleaves an amino acid from Ang II to produce the heptapeptide vasodilator Ang 1-7[11][16], and the balance between ACE and ACE2 is critical for controlling Ang II levels[20]. In the heart, mast cells, endothelial cells and interstitial mesenchymal cells express this enzyme[66], and in the kidney, mesenchymal cells and vascular smooth muscle cells also express this enzyme[23]. In cardiac, vascular and renal tissues, particularly in disease states, inhibition of enzyme-mediated Ang II production has emerged as an alternative pathway to ACE[3][23][38] (Figure 1).Ang II can be degraded by other aminopeptidases in the circulation to Ang (2-8) (Ang III) and Ang (3-8) (Ang IV). Ang III has been shown to play a role in increasing blood pressure and vasopressin release [10][51] and to stimulate the expression of proinflammatory mediators in cultured kidney cells [54] in a similar but less potent manner than Ang II. Ang IV exerts its protective effects by increasing blood flow to the kidneys[21] and brain[32].
Figure 1: Renin Angiotensin System (RAS). Angiotensin I is cleaved by ACE or chymotrypsin to produce the active octapeptide Ang II, which acts through AT1 and AT2 receptors. Angiotensin II levels are also regulated by ACE2, which cleaves angiotensin II to produce the vasodilatory heptapeptide Ang 1-7. AGT, angiotensinogen; ACE, angiotensin-converting enzyme; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; ACEi, angiotensin-converting enzyme inhibitor; ARB , angiotensin II receptor blockers.
Ang II in the circulation causes an increase in blood pressure and affects the renal tubules → which retain sodium and water[8][29]. One of the most important advances in the field over the past two decades has been the discovery of local or tissue RAS. local systems are characterised → by the presence of RAS components in multiple organs, including the heart[67], kidney[30], brain[39] and pancreas[18], as well as reproductive[63], lymphoid[26] and adipose tissue[27]. The local RAS performs different functions in each organ; it can operate independently → functionally, as in the adrenal glands and the brain, or it can interact closely with the circulating RAS, as in the heart and the kidneys. In addition, a functional intracellular RAS has been identified[14] [50]. The discovery of local and intracellular RAS highlights several prominent non-hemodynamic effects of Ang II, including pro-inflammatory, proliferative and pro-fibrotic activities.Ang II promotes reactive oxygen species (ROS) generation, cell growth, apoptosis, cell migration and differentiation, extracellular matrix remodelling, regulation of gene expression and can activate a variety of intracellular signalling pathways, leading to tissue damage[55]. In tissues such as kidney, heart and vasculature, Ang II induces an inflammatory response by promoting → facilitating the expression of pro-inflammatory chemokines, leading to the accumulation of immune cells in tissues[61]. In hypertension, a deleterious → harmful amplification mechanism occurs in the kidney, in which → Ang II induces the expression of renal angiotensinogen, thereby → thereby inducing its own synthesis[31].
2.2 Angiotensin Receptors
Angiotensin II acts through two distinct G-protein-coupled receptors (i.e., angiotensin type 1 and type 2 (AT1 and AT2) receptors)[24][48]. The single AT1 receptor is expressed in human cells, whereas two isoforms, AT1A and AT1B, exist in rats and mice, which share 95% sequence similarity. Abbreviations of technical terms are explained at the time of first use. The article follows the principles of objectivity, comprehensibility and logical structure, clear and objective language, conventional structure and format, formal register, balanced presentation, precise word choice and grammatical correctness.The AT1A receptor is the closest murine receptor to the human AT1 receptor, and is expressed in kidney, heart, brain, adrenal glands, vascular smooth muscle, liver, and several other tissues[9]. In contrast, AT1B is predominantly expressed in the anterior pituitary and the suprarenal glomerular zone of the adrenal glomerulus[43].AT1A produces most of the conventional effects of Ang II, such as an increase in blood pressure[25], aldosterone release from the adrenal glomerular epithelial cells[1], proximal tubular cell salt retention[62], and stimulation of the sympathetic nervous system via receptors in the brain[12].AT1B can in the AT1A receptor regulation of blood pressure in the absence of AT1A receptors[43]. The angiotensin II type II receptor is commonly expressed in developing foetal tissues. However, after birth, the expression of this receptor decreases and remains low in various adult tissues such as adrenal medulla, uterus, ovary, vascular endothelium and different brain regions[60]. In the cardiovascular and renal systems, AT1 and AT2 receptors are counter-regulatory[58]. Binding of angiotensin II to AT2 receptors leads to vasodilation of resistance and conduit arteries, which in turn improves arterial re-modelling in humans and mice.AT2 receptors are upregulated in cardiovascular injury and play an important role in preventing ischaemia-reperfusion injury and acute myocardial infarction [58]. In addition, AT2 receptors are protective against renal fibrosis and ischaemic kidney injury, as their absence exacerbates kidney injury and reduces survival in a mouse model of renal ablation[5]. In response to angiotensin II, the AT2 receptor has also been suggested to have pro-inflammatory functions by stimulating the NF-κB pathway[15][53][69].Finally, AT1 and AT2 receptors are binding sites for Ang III, while AT4 receptors are specific to Ang IV and are found in the brain, kidney, heart, and blood vessels[13].
3. Does brain ageing affect cognitive function?
As a result of the discovery of a circulatory system-independent RAS, research has begun to investigate the role of the brain RAS, particularly its role in the pathophysiology of Alzheimer's disease, the most common form of dementia. The main risk factors for Alzheimer's disease are age, accumulation of misfolded proteins in the aging brain, and deterioration of the cardiovascular system. Accumulation of amyloid (α-β) peptides leads to oxidative and inflammatory damage, resulting in energy failure and synaptic dysfunction [36][49].
Increased ACE activity has been observed in homogenates of postmortem brain tissue from patients with Alzheimer's disease and correlates with A-beta plaque burden and severity of amyloid angiopathy [2]. Increased ACE and Ang II immunoreactivity has been reported in neuronal and perivascular periphery of parietal and frontal cortical vessels in the brain of patients [37][56].Increased ACE activity may reduce cerebral perfusion characteristics by increasing Ang II production [28]. In the Tg2576 mouse model of Alzheimer's disease, prophylactic treatment with AT1 receptor blockers reduced Alzheimer's-like neuropathology and attenuated the aggregation of A-beta peptides into extracellular amyloid plaque deposits in the brain [68]. In patients with Alzheimer's disease, treatment with ACEi (e.g., perindopril and captopril) that cross the blood-brain barrier (BBB) has been shown to have a beneficial effect on the rate of cognitive decline [42]. A cohort analysis of 819,491 patients (predominantly male) diagnosed with dementia or Alzheimer's disease showed that ARB treatment significantly reduced the incidence and progression of dementia or Alzheimer's disease, as measured by nursing home admission, compared with ACEi or other medications for hypertension or vascular disease. In addition, the combined use of ARBs and ACEi reduces the risk of worsening Alzheimer's or dementia [34]. The protective effects of anti-angiotensin-converting enzyme inhibitors slow down the cognitive deterioration of the aging brain in a long-lasting and stable manner. Blockade of AT1 receptors may also promote the conversion of endogenous Ang II to Ang III and Ang IV. In this case, activation of AT4 receptors by Ang IV may produce memory-enhancing effects [71].
4. Clinical significance
The synthesis of Captopril, the first orally active ACEi [44], stimulated the development of a new therapeutic paradigm and opened a new era of research to understand the clinical significance of the RAS system, and the efficacy of RAS blockers in the treatment of hypertension, heart failure, and renal disease has been gradually demonstrated [46]. The treatment of hypertension has also benefited from the subsequent discovery of Ang II antagonists, which selectively block AT1 receptor activation without affecting vasodilatory kinins, thereby lowering blood pressure, even in patients with no increase in Ang II. Inhibition of RAS activity using ACEi or ARB has beneficial effects in patients with left ventricular dysfunction or systolic heart failure. Treatment with ACEi or ARB reduces the risk of mortality and adverse cardiovascular outcomes in patients at high risk of coronary heart disease, independent of blood pressure control [73]. Intensive treatment with ACEi in diabetic patients with micro-albuminuria may be nephroprotective and cardioprotective. Comprehensive interventions in non-diabetic patients with chronic kidney disease include the use of doses higher than those recommended for blood pressure control.
The challenge in the coming years will be to determine whether these drugs can be translated into new medical applications. Selective blockade of AT1 receptors alone or in combination with ACEi is more protective against cerebrovascular damage, which opens up new prospects for the health of patients with cognitive impairment. Based on recent studies in transgenic animals and aged rats chronically treated with ACEi or ARB, drugs that interfere with Ang II synthesis and/or bioactivity may be promising candidates for modulating the aging signalling cascade and prolonging lifespan. The excellent safety record of millions of patients with hypertension, heart and renal failure on long-term use of ACEi and ARB suggests that long-term use of these drugs may be effective in preventing the gradual deterioration of organ function associated with aging without significant side effects. Whether this contributes to healthy ageing and longevity is currently only a matter of speculation.
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