The renin–angiotensin–aldosterone system, glucose metabolism and diabetes

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In diabetes mellitus (DM), the circulating renin–angiotensin system (RAS) is suppressed, but the renal tissue RAS is activated. Hyperglycemia increases tissue angiotensin II (Ang II), which induces oxidative stress, endothelial damage and disease pathology including vasoconstriction, thrombosis, inflammation and vascular remodeling. In early DM, the type 1 Ang II (AT1) receptor is upregulated but the type 2 Ang II (AT2) receptor is downregulated. This imbalance can predispose the individual to tissue damage. Hyperglycemia also increases the production of aldosterone, which has an unknown contribution to tissue damage. The insulin resistance state is associated with upregulation of the AT1 receptor and an increase in oxygen free radicals in endothelial tissue caused by activation of NAD(P)H oxidase. Treatment with an AT1 receptor blocker normalizes oxidase activity and improves endothelial function. An understanding of the tissue renin–angiotensin–aldosterone system, which is a crucial factor in the progression of tissue damage in DM, is imperative for protection against tissue damage in this chronic disease.

Introduction

Diabetes mellitus is a chronic metabolic disorder that results in hyperglycemia and the development of complications in target organs, including retinopathy, neuropathy, nephropathy and cardiovascular disease. Of these complications, diabetic nephropathy, the most common etiology of chronic kidney disease in western countries, is associated with the highest mortality [1]. The initial stages of diabetic nephropathy are characterized pathologically by glomerular and tubular cell hypertrophy with a thickening of basement membranes, and clinically by the development of hyperfiltration and microalbuminuria. Diabetic nephropathy progresses, usually over the course of several years, to glomerulosclerosis with an accumulation of extracellular matrix proteins in the glomerular mesangium. As the glomerular filtration rate declines, progressive tubulointerstitial fibrosis leads to end-stage renal disease. The high mortality of individuals with DM can be attributed both to end-stage renal disease and to cardiovascular disease, especially in type 2 DM [2]. Approximately 80% of individuals with diabetic end-stage renal disease are affected with hypertension, which accelerates the progression rate of renal disease [3].

The renin–angiotensin system (RAS) is a coordinated hormonal cascade that is initiated through biosynthesis of the enzyme renin in the juxtaglomerular cells of the renal afferent arteriole. Renin is secreted from juxtaglomerular cells by an exocytotic process and acts enzymatically on angiotensinogen (Agt) to cleave an inactive decapeptide, Ang I, which is further catabolized by angiotensin-converting enzyme (ACE) to the biologically active peptide Ang II. Renin is thought to have no direct biological (non-enzymatic) action, although a prorenin or renin receptor has been recently identified 4, 5, 6. Although Agt is the only known substrate for the formation of Ang II, other enzymes (e.g. cathepsins and chymase) in addition to renin can catalyze its formation. Ang II exerts most of its actions, including vasoconstriction, renal tubule sodium reabsorption, growth promotion, cellular dedifferentiation, inhibition of renin release, aldosterone secretion, thirst and sympathetic outflow, using the AT1 receptor.

Recently, the functions of another major Ang II receptor, AT2, have been partially characterized 7, 8, 9, 10, 11, 12, 13. Ang II stimulation of the AT2 receptor generally opposes Ang II actions mediated via the AT1 receptor, most notably by promoting vasodilation and growth inhibition. Vasodilation mediated by the AT2 receptor is thought to occur via the production of bradykinin and nitric oxide (NO) mainly in peripheral microvessels (e.g. coronary and mesenteric vessels) 13, 14.

Ang II is metabolized into biologically inactive peptide fragments by circulating and tissue peptidases, although at least three of the metabolic products of Ang II have been shown to have biological activity. Ang II can be degraded to des-aspartyl 1-Ang II (Ang III), which is equipotent with Ang II in its interaction with the AT1 receptor, but is less efficacious than Ang II in vivo because of its accelerated metabolism in the circulation. A second Ang II metabolic product, the hexapeptide Ang IV, has been shown to cause both vasodilation and natriuresis 15, 16, 17, 18. A third Ang II metabolite, Ang (1–7), can be formed directly from Ang II by the action of a recently identified enzyme, angiotensin converting enzyme-2 (ACE-2) 19, 20. Ang (1–7) releases NO and prostaglandins, causing vasodilation, natriuresis and the inhibition of cellular proliferation 21, 22, 23, 24, 25, 26. Thus, several of the components of the RAS – namely, the AT2 receptor, Ang (1–7) and Ang IV – act in opposition to the AT1 receptor.

Aldosterone is a mineralocorticoid hormone that is synthesized and secreted by the zona glomerulosa of the adrenal cortex. Aldosterone acts at mineralocorticoid receptors, largely in the transport of epithelial cells in the kidney, salivary glands and gastrointestinal tract, where it increases sodium absorption and potassium and hydrogen ion secretion. Recently, aldosterone has been implicated in non-genomic actions, such as cell proliferation, cytokine release, inflammation and fibrosis. Aldosterone is mainly regulated by Ang II and potassium, but it can be also stimulated acutely by adrenocorticotropic hormone.

The RAS has been strongly implicated in the pathophysiology of diabetic renal disease on the basis of the therapeutic ability of ACE inhibitors and AT1 receptor blockers to decrease microalbuminuria and the progression of diabetic nephropathy to end-stage renal disease 27, 28, 29, 30, 31, 32, 33, 34, 35. The circulating (systemic) RAS is suppressed in DM, however, as reflected by measurements of plasma renin activity and Ang II concentrations. Because all of the components of the RAS are present in the kidney and intrarenal generation of Ang II has been demonstrated, Ang II has been considered to be a local paracrine substance involved in the control of renal function 36, 37, 38, 39, 40, 41, 42, 43, 44, 45. Current data suggest that either activation of the local tissue RAS in the kidney independent of the systemic circulation, or an increase in renal sensitivity to Ang II at the AT1 receptor, or both, occurs in DM.

In this review, we emphasize new developments in our understanding of the role of the renin–angiotensin–aldosterone system (RAAS) in glucose metabolism and DM.

Section snippets

Physiological, biochemical and molecular background

In the kidney, Agt mRNA and protein have been localized to the proximal tubule cells. It is thought that Agt derived from these cells provides the substrate for intratubular and renal interstitial production of Ang I and Ang II [36]. Indeed, it is possible that Agt is secreted directly into the proximal tubule lumen, where it could interact with renin, which is also synthesized in these cells. If Ang I is formed in the proximal tubule, it could be converted to Ang II by ACE on the brush border

The RAS in DM

Whereas the circulating RAS is usually normal or suppressed in DM, the renal tissue RAS seems to be activated 49, 50. In rats with spontaneous or streptozotocin-induced diabetes, renin mRNA and protein expression are increased in both juxtaglomerular and proximal tubule cells, accompanied by a rise in Ang II production [51]. Renal levels of Agt mRNA are also raised, suggesting that the proximal tubule increases Agt synthesis 50, 51. A glucose-response element has been identified in the Agt gene

The RAS and adipose tissue in the insulin resistance syndrome

The term ‘insulin resistance syndrome’ identifies a condition in which several metabolic risk factors (e.g. insulin resistance, dyslipidemia, obesity, hypertension, hypercoagulation and hyperuricemia) are clustered, resulting in an increased risk of atherosclerotic cardiovascular disease. Current knowledge indicates that insulin resistance constitutes a common link among these risk factors, leading to the hypothesis that it has a pathogenetic role in this syndrome [67].

In fact, insulin

Excess of aldosterone and DM

Epidemiological studies on the prevalence of abnormal glucose metabolism among individuals with primary aldosteronism (PA) are scarce and limited to small population studies. In 1965, Conn and colleagues [76] reviewed a group of 39 individuals with PA and noted that 21 (54%) had impaired glucose tolerance, as assessed by an oral glucose tolerance test. The available data indicate that the prevalence of impaired glucose metabolism in PA is about 15–25%; furthermore, in the year 2000, the Expert

Aldosterone and diabetic renal disease

Aldosteronism has long been considered to be a relatively benign form of hypertension associated with a low incidence of organ complications. These effects were generally ascribed to the suppression of renin activity that occurs as a result of an aldosterone-generated volume expansion. More recent studies, however, have shed light on the potential role of aldosterone in inducing accelerated vascular damage both through effects mediated by mineralocorticoid receptors and through non-genomic

Concluding remarks

We have presented evidence showing that in DM the RAS is activated at the tissue level even though the circulating RAS is suppressed. Activation of the RAS leads to tissue damage, including proteolysis, inflammation and fibrosis. At the tissue level, cellular destruction may be related to the activation of NAD(P)H oxidase by Ang II, leading to the liberation of reactive oxygen species that decrease NO bioavailability. Thus, target organ damage seems to be due, at least in part, to activation of

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