Renin-angiotensin-aldosterone system and the aging kidney

Abstract

Human senescence induces changes in the renin-angiotensin-aldosterone system (RAAS) which consists of a substantial decrease in its plasma activity. Consequently, the distal tubule´s capability of handling sodium and potassium is significantly reduced in the elderly, while distal tubule acidification is slightly delayed but preserved in this age group. Several studies in animal models support the hypothesis that senile renal structural changes could be induced by the local production of angiotensin II, and also that enalapril significantly decreases senile mesangial expansion, glomerulosclerosis and peritubular and medullar interstitial sclerosis. The same applies to several highly prevalent diseases in the elderly, such as hypertension, obesity, cardiac insufficiency, chronic nephropathy and dementia. In conclusion, the relationship between the RAAS and senescence is complex, since not only does aging cause many changes on this hormonal system, but also RAAS overactivity seems to be one of the main inducing mechanisms for normal senescence, and for many prevalent diseases in the elderly.

Keywords::

• aging
• aldosterone
• angiotensin
• renin
• senescence

Influence of aging on RAAS

Human senescence induces changes in the renin hormone, which consists of a substantial reduction in its plasma activity. This reduction is more pronounced in the upright posture and sodium-volume depletion settings, where its serum levels are relatively lower than expected [1–3]. In rat aging models, this reduced plasma renin activity was documented to be associated with a reduction in renin synthesis in their juxtaglomerular apparatuses, which seem to be damaged during senescence [4]. All these chances consequently lead to a reduction in the function of the renin–angiotensin system (RAS) in the elderly [1–4]. However, despite the renin–angiotensin–aldosterone system (RAAS) activity decrease documented in the elderly, angiotensin II local secretion at the renal parenchyma is markedly increased. This phenomenon has been attributed to the histological renal modifications induced by the senile glomerulosclerosis process and also associated with the vascular hemodynamic alterations suffered by the aged kidney [5–7]. Moreover, since angiotensin II represents a key molecule in renal physiopathological processes by causing inflammation, cell growth and reactive oxygen species generation (oxidative stress) at cellular and mitochondrial levels, this situation could represent a vicious cycle that leads to renal tissue deterioration [6]. It is worth highlighting that since angiotensin II characteristically stimulates a preponderant efferent arteriole vasoconstriction and also proximal tubule sodium reabsorption, this senile increase in angiotensin II local secretion could explain two characteristic physiological aspects of the aged kidney [6–8]: an increased glomerular filtration fraction and proximal tubule sodium reabsorption characteristically observed in the aged kidney compared with that documented in the young kidney. The adrenal gland synthesizes the aldosterone hormone, which regulates renal and colonic sodium reabsorption, potassium secretion in both organs and also tubular distal acidification in the kidney. This hormone shows low serum levels as well as a reduced distal tubule response in the elderly. Senile lower levels of aldosterone have been observed either on an unrestricted salt diet or on salt restriction and walking settings [1,9,10]. The collecting duct is normally responsible for the final control of urinary sodium, potassium and proton excretion. The reabsorption of sodium and secretion of potassium and proton are stimulated by aldosterone, which induces an increase in the number and activity of the apical sodium (Na+) and potassium (K+) channels as well as in the basolateral sodium–potassium ATPase pumps (principal cells) and apical H+ ATPase pumps (intercalated cells). Thus, the amount of sodium entering the tubular cells from the luminal fluid (by means of Na+ channels) increases the intracellular sodium concentration, which is then expelled from the cells to the interstitium (by means of Na+ K+ ATPase pumps). This generates a negative electrical potential in the lumen responsible for stimulating K+ (by means of K+ channels) and H+ (by means of H+ ATPase pumps) secretion from principal and intercalated cells, respectively [6].

It is relevant to mention that the particular physiology of the distal tubules in the elderly could be mainly attributed to the senile aldosterone changes mentioned above. First, there is a reduction of sodium reabsorption by the senile collecting ducts, which explains part of the increased sodium urinary excretion observed in the elderly [5,8]. This phenomenon makes old people susceptible to hypovolemia and/or hyponatremia (entity known as senile sodium leakage hyponatremia) when they are exposed to strict low sodium diets or potent diuretics [5]. Second, there is a reduced potassium secretion capability in urine as well as in feces in the elderly [5,8]. This physiological situation predisposes old people to easily develop hyperkalemia, particularly when they are on medications such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), aldosterone antagonists or their combination [5,8]. Although the distal tubule capability to handle sodium and potassium is significantly reduced in the elderly compared to these renal functions in the young, distal tubule acidification is slightly delayed but preserved in healthy old people in comparison with young people. This phenomenon has been attributed to the fact that ammonium ion excretion is less efficient or takes longer to reach its peak in response to an acute acid load in the elderly, though there is no absolute functional deficit in this tubular capability with senescence [5,8,10]. Finally, serum adrenocorticotropic hormone levels in healthy old people are the same as in young people, although its secretion rhythm varies [11]. Besides aging, other important variables which influence the RAAS are family genetics, race and gender. Studies in first-degree relatives of patients with essential hypertension have demonstrated higher plasma renin levels and a decreased ability to excrete sodium load when compared to first-degree normotensive relatives. Afro-American people have a decreased ability to excrete a sodium load and a greater rise in blood pressure with sodium loading than do whites. It has been suggested that the heritability of hypertension is directly related to a genetic influence on renin levels, the increase of which results in subtle chronic increase in RAAS activity and decrease in sodium excretion kidney ability [12]. Finally, extensive evidence suggests that the protective pathways of the RAAS are enhanced in young women, including the angiotensin type 2 receptor, which mediates vasodilatory and natriuretic effects. In this sense, recent studies in animal models have documented that acute angiotensin type 2 receptor stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in the glomerular filtration rate in female hypertensive rats [13].

RAAS influence on aging

From the age of 30, the process of glomerular replacement by fibrous tissue (senile glomerulosclerosis) starts affecting an increasing number of glomeruli (around 25% of the whole population). Concomitantly, mesangium expands to nearly 12% and some glomerular capillaries suffer obliteration. Renal tubules undergo irregular thickening of their basal membrane, with increasing zones of tubular atrophy and fibrosis [5,11].

Several studies support the hypothesis that all the above-described senile renal structural changes could be partially induced by angiotensin II local production. Angiotensin II can activate many intracellular pathways that induce the proliferation of a variety of cells and can also induce and amplify the inflammatory response in mesangial, glomerular and tubular tissues. In the latter, it has also been demonstrated that they express the genes of several cytokines, chemokines and other inflammatory mediators including renin-angiotensin ones. Additionally, it has already been documented that angiotensin II stimulates the production of chemoattractant proteins, which are involved in the inflammatory process [14].

In this sense, Ferder et al. have already demonstrated that enalapril significantly decreased aging-related mesangial expansion, glomerulosclerosis and interstitial sclerosis in mice. The beneficial effect of ACEIs and angiotensin II receptor antagonists (ARBs) on aging in mice is independent of their antihypertensive action, since using doses that do not modify the blood pressure in experimental models based on hypertensive animals also slow the appearance of glomerulosclerosis. Blocking angiotensin II formation or action reduces oxidative stress in the mitochondria and protects the integrity of renal tissues and kidney functions. Angiotensin II induces excessive release of vascular superoxide radicals generated by stimulation of NADH/NADPH oxidase which inactivates nitric oxide. Thus, inhibition of angiotensin II formation would attenuate oxidative stress and improve vasodilatation by permitting nitric oxide production, and this lower oxidative stress reduces inflammation, cytokine and growth factor production and the process of fibrosis. However, it is important to point out that no current data exist to support that angiotensin II blocking or suppression can retard renal aging in human beings [14–20]. Additionally, Remuzzi et al. have documented that a targeted disruption of the Agtr1a gene, which encodes angiotensin II type 1A receptors (Ang II/AT1A), results in a marked prolongation of life span in mice, since these mice developed less cardiac and vascular injury and their organs displayed less oxidative damage than wild-type mice. The longevity phenotype was associated with an increased number of mitochondria and upregulation of the prosurvival genes (e.g., Klotho gene), nicotinamide phosphoribosyltransferase and sirtuin 3 in the kidney. In cultured tubular epithelial cells, angiotensin II downregulated sirtuin 3 mRNA, and this effect was inhibited by ARBs. These results suggest that the Ang II/AT1 pathway might be influenced to increase life span in mammals [21–25].

RAAS influence on senile prevalent diseases

There are highly prevalent diseases in the elderly (hypertension, obesity, cardiac insufficiency, chronic kidney disease and dementia) that have been associated, at least in part, to inappropriate mineralocorticoid receptor activation, since this activation triggers deleterious responses in various tissues, including vessels, heart and brain, hence promoting vascular inflammation, cardiovascular remodeling, endothelial dysfunction and oxidative stress [24,25].

Angiotensin II and related peptides are also proinflammatory and profibrotic agents. Increased generation of cellular reactive oxygen species and activation of redox-sensitive signaling cascades are critical events involved in angiotensin II actions. After binding to its AT1 receptors, angiotensin II triggers intracellular superoxide production. Under normal physiological conditions, this pathway is closely regulated but under conditions associated with the overactivation of RAAS, such as hypertension, diabetes and normal aging, angiotensin II-dependent oxidant generation becomes a significant contributor to cell oxidation and tissue damage. Due to the above-mentioned reasons, RAS blockade with ACEIs or ARBs in the setting of hypertension, heart failure and chronic renal failure, provide cardiac and renal benefits not limited to their antihypertensive effect [26].

Moreover, it has been suggested that aldosterone is one of the agents controlling vascular tone because recent evidence suggests that this mineralocorticoid hormone may cause vasoconstriction under pathophysiological conditions, through modulating the gene expression and activity of endothelin-1, glucose-6-phosphate dehydrogenase and Rho kinase, as well as by altering the phosphorylation and activity of endothelial nitric oxide synthase [27]. Additionally, several lines of evidence suggest that estrogen favorably modulates the RAAS, while estrogen deficiency due to menopause may contribute to its overactivity. This phenomenon could explain the increased prevalence of hypertension in elderly women [28].

Regarding obesity, epidemiological studies have shown a clear association between aldosterone levels and the incidence of metabolic syndrome. Recent work has revealed functional mineralocorticoid receptors in adipose tissue, where they mediate the effects of aldosterone, displaying important and specific functions involving adipose differentiation, expansion and proinflammatory capacity [24].

The ACE gene is a locus clearly associated with pathogenesis and progression of chronic kidney disease and with response to treatment with drugs that directly interfere with the RAS. The II genotype is protective against the development and progression of diabetic nephropathy and is associated with a slower progression of nondiabetic proteinuric renal disease. ACEs are particularly effective at the stage of normoalbuminuria or microalbuminuria in both type I and type II diabetic patients with the II genotype, whereas the DD genotype is associated with a better response to ARB therapy in overt nephropathy in type II diabetes and to ACEs in male patients with nondiabetic proteinuric nephropathies. The role of other RAS or non-RAS polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Thus, evaluating the ACE I/D polymorphism would be a reliable tool to identify patients at risk and those who may benefit the most of pharmacological renoprotective therapy [29].

Moreover, animal studies have suggested that angiotensin II promotes the production of amyloid in the brain and that IECAs or ARBs may decrease amyloid-β oligomerization. In a clinical study, Nien-Chen Li et al. documented that ARBs were associated with a significant reduction in the incidence and progression of Alzheimer’s disease and dementia compared with ACEs or other cardiovascular drugs in a predominantly male population. Additionally, Ihab Hajjar et al. found that treatment with ARBs was associated with less Alzheimer disease-related pathology on autopsy evaluations [30].

Conclusion

The relationship between RAAS and senescence is complex since not only does aging induce many changes on this hormonal system, but also RAAS overactivity seems to be one of the main inducing mechanisms for normal senescence and for many prevalent diseases in the elderly.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.