Renin-angiotensin-aldosterone system in insulin resistance and metabolic syndrome

Abstract

Obesity and its consequent complications such as hypertension and metabolic syndrome are increasing in incidence in almost all countries. Insulin resistance is common in obesity. Renin- angiotensin system (RAS) is an important target in the treatment of hypertension and drugs that act on RAS improve insulin resistance and decrease the incidence of type 2 diabetes mellitus, explaining the close association between hypertension and type 2 diabetes mellitus. RAS influences food intake by modulating the hypothalamic expression of neuropeptide Y and orexins via AMPK dephosphorylation. Estrogen reduces appetite by its action on the brain in a way similar to leptin, an anorexigenic action that seems to be mediated via hypothalamic pro-opiomelanocortin (POMC) neurons in the arcuate nucleus and synaptic plasticity in the arcuate nucleus similar to leptin. Estrogen stimulates lipoxin A4, a potent vasodilator and platelet anti-aggregator. Since both RAS and estrogen act on the hypothalamic neuropeptides and regulate food intake and obesity, it is likely that RAS modulates LXA4 synthesis. Thus, it is proposed that Angiotensin-II receptor blockers and angiotensin-converting enzymes and angiotensin-II antagonists may have the ability to augment LXA4 synthesis and thus bring about their beneficial actions.

Keywords: angiotensin; diabetes mellitus; food intake; free radicals; hypertension; lipoxin A4; metabolic syndrome; oestrogen; renin.

Figures

Figure 1

Scheme showing the involvement of renin-angiotensin-aldosterone system on food intake, energy expenditure, water, salt balance and blood pressure Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin–angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin stimulates the release of aldosterone from the adrenal cortex that promotes sodium retention in the distal nephron, in the kidney, which drives blood pressure up. Angiotensin, an oligopeptide hormone, derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. Human angiotensinogen is 452 amino acids long and is converted to angiotensin-I by the action of renin that is produced by the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure at the juxtaglomerular cells, or decreased delivery of Na+ and Cl- to the macula densa. If less Na+ is sensed by the macula densa, renin release by juxtaglomerular cells is increased. Angiotensin-I has no biological activity and exists solely as a precursor to angiotensin II. Angiotensin-I is converted to angiotensin-II (Ang-II) by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the kidney. ACE found in other tissues of the body such as lungs, but activation here promotes no vasoconstriction, as the level of angiotensin-II is below physiological levels of action. Angiotensin-II acts as an endocrine, autocrine/paracrine, and intracrine hormone. ACE inhibitor drugs decrease the rate of Ang-II production. Angiotensin II increases blood pressure. ACE inhibitor drugs are major drugs against hypertension. The action of Ang-II itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin-II AT1 receptors. Nitric oxide is a potent inhibitor of ACE. Ang-II also acts on the pituitary gland to induce the release of ADH (antidiuretic hormone) that enhances water absorption in the collecting ducts of the kidney. It is known that Ang-II has proinflammatory actions, enhances the production of IL-6 and TNF-α and augments free radical generation reactive oxygen species, ROS). Ang-II does influence food intake and energy expenditure apart from its influence on water, salt balance, and blood pressure. Ang-II receptors are present in the brain and especially in the hypothalamus. Ang-II acts in the brain to promote negative energy balance by altering the hypothalamic circuits regulating energy balance that include increased uncoupling protein-1 and β(3)-adrenergic receptor expression in brown adipose tissue and β3-adrenergic receptor expression in white adipose tissue, suggesting enhanced sympathetic activation and thermogenesis; decrease food intake, increase in energy expenditure, and finally Ang II type-1a receptor-dependent Ang-II signaling reduces food intake by suppressing the hypothalamic expression of neuropeptide Y and orexins via AMPK dephosphorylation. Ang-II regulates body weight through mechanisms related to increased peripheral metabolism and independent of elevations in blood pressure. In addition and in a paradoxical fashion, angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity, have increased energy expenditure, with reduced fat mass and improved glucose clearance, events that explain the beneficial actions of angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers in the prevention or postponement of the development of obesity, type 2 diabetes mellitus and metabolic syndrome in hypertensives. In a transgenic mouse model overexpressing renin in the liver (RenTgMK) led to constitutively elevated plasma angiotensin II (four- to sixfold increase vs. wild type). RenTgMK mice developed glucose intolerance despite low levels of adiposity and low plasma insulin levels. The transgenics also had lower plasma triglyceride levels. Glucose intolerance in RenTgMK transgenic mice fed a low-fat diet was comparable to that observed in high fat-fed wild type mice, suggesting that overexpression of renin and associated hyperangiotensinemia impair glucose tolerance in a diet-dependent manner lending support to the concept that the involvement of renin–angiotensin system (RAS) in the pathogenesis of diabetes and insulin resistance is independent of changes in fat mass. It is noteworthy that estrogen stimulates the production of lipoxin A4 (LXA4), a potent vasodilator, platelet antiaggregator and anti-inflammatory molecule formed from arachidonic acid (AA, 20:4 n-6). LXA4 suppresses the production of IL-6 and TNF-α and could antagonize the pro-inflammatory and pro-hypertensive actions of angiotensin-II. High-fat diet induced apoptosis of hypothalamic neurons could be blocked by the presence of appropriate amounts of LXA4 and it (LXA4) could also suppress the formation of ROS in the hypothalamus. LXA4 induces the production of endothelial nitric oxide (eNO), which, in turn, neutralizes ROS. NO is a vasodilator, possesses antihypertensive action and acts as platelet antiaggregator and serves as a neurotransmitter. Both NO and LXA4 may regulate hypothalamic neurotransmitters and other peptides such as serotonin, dopamine, NPY, CRH, and melanocortins. Acetylcholine, the principal neurotransmitter of vagus, stimulates NO generation and possibly, LXA4, and it (acetylcholine) has potent anti-inflammatory actions. The antihypertensive action of renal sympathetic denervation for the treatment of resistant hypertension could be attributed at least, in part, to concomitant increase in the tone of parasympathetic nervous system (increase in vagal tone) since normally a balance is maintained between sympathetic and parasympathetic nervous systems, which leads to increase in the production of acetylcholine and consequent increase in NO and LXA4 generation.