The renin–angiotensin system and diabetes: An update

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Abstract

In the past few years the classical concept of the renin–angiotensin system (RAS) has experienced substantial conceptual changes. The identification of the renin/prorenin receptor, the angiotensin converting enzyme homologue ACE2 as an angiotensin peptide processing enzyme, Mas as a receptor for Ang-(1–7) and the possibility of signaling through ACE, have contributed to switch our understanding of the RAS from the classical limited proteolysis linear cascade to a cascade with multiple mediators, multiple receptors, and multi functional enzymes. In this review we will focus on the recent findings related to RAS and, in particular, on its role in diabetes by discussing possible interactions between RAS mediators, endothelium function, and insulin signaling transduction pathways as well as the putative role of ACE2-Ang-(1–7)-Mas axis in disease pathogenesis.

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Most cited references 150

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The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.

H H Parving, H Lehnert, J Bröchner-Mortensen … (2001)

Microalbuminuria and hypertension are risk factors for diabetic nephropathy. Blockade of the renin-angiotensin system slows the progression to diabetic nephropathy in patients with type 1 diabetes, but similar data are lacking for hypertensive patients with type 2 diabetes. We evaluated the renoprotective effect of the angiotensin-II-receptor antagonist irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria. A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this multinational, randomized, double-blind, placebo-controlled study of irbesartan, at a dose of either 150 mg daily or 300 mg daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 microg per minute and at least 30 percent higher than the base-line level. The base-line characteristics in the three groups were similar. Ten of the 194 patients in the 300-mg group (5.2 percent) and 19 of the 195 patients in the 150-mg group (9.7 percent) reached the primary end point, as compared with 30 of the 201 patients in the placebo group (14.9 percent) (hazard ratios, 0.30 [95 percent confidence interval, 0.14 to 0.61; P< 0.001] and 0.61 [95 percent confidence interval, 0.34 to 1.08; P=0.081 for the two irbesartan groups, respectively). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150-mg group, and 141/83 mm Hg in the 300-mg group (P=0.004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups). Serious adverse events were less frequent among the patients treated with irbesartan (P=0.02). Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.

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International union of pharmacology. XXIII. The angiotensin II receptors.

M de Gasparo, K Catt, T Inagami … (2000)

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

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Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes.

C E Mogensen (1984)

We studied whether microalbuminuria (30 to 140 micrograms of albumin per milliliter) would predict the later development of increased proteinuria and early mortality in Type II diabetics. During 1973, morning urine specimens of diabetic clinic patients 50 to 75 years of age whose disease had been diagnosed the age of 45 were examined for albumin level by radioimmunoassay. Seventy-six patients with albumin concentrations of 30 to 140 micrograms per milliliter were identified for long-term follow-up. They were compared with normal controls, diabetic patients with lower albumin concentrations (75 patients with concentrations less than 15 micrograms per milliliter and 53 with concentrations of 16 to 29 micrograms per milliliter), and 28 diabetic patients with higher concentrations (greater than 140). Age, duration of diabetes, treatment method, fasting blood glucose level, blood pressure, height, and weight were determined for the four diabetic groups. After nine years the group with albumin concentrations of 30 to 140 micrograms per milliliter was more likely to have clinically detectable proteinuria (greater than 400 micrograms per milliliter) than were the groups with lower concentrations. Mortality was 148 per cent higher in this group than in normal controls--comparable to the increase (116 per cent) in the group with heavy proteinuria (albumin levels greater than 140 micrograms per milliliter). In addition, mortality was increased 76 per cent in the group with albumin levels of 16 to 29 micrograms per milliliter and 37 per cent in the group with levels below 15. We conclude that microalbuminuria in patients with Type II diabetes is predictive of clinical proteinuria and increased mortality.

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Author and article information

Journal

Journal ID (nlm-ta): Vasc Health Risk Manag

Journal ID (publisher-id): Vascular Health and Risk Management

Title: Vascular Health and Risk Management

Publisher: Dove Medical Press

ISSN (Print): 1176-6344

ISSN (Electronic): 1178-2048

Publication date (Print): August 2008

Volume: 4

Issue: 4

Pages: 787-803

Affiliations

[1 ]Laboratório de Endocrinologia, Departamento de Clínica Médica

[2 ]Departamento de Ciências Biológicas, Centro Universitário de Belo Horizonte, UNIBH, Belo Horizonte, MG, Brazil

[3 ]Hospital Life Center, Belo Horizonte, MG, Brazil

[4 ]Laboratório de Hipertensão, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, MG, Brazil

[5 ]Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil

Author notes

Correspondence: Ana Cristina Simões Silva, Avenida Bernardo Monteiro, 1300 apto 1104, Bairro Funcionários, Belo Horizonte, Minas Gerais, Brazil, 30150-281, Tel +55 31 7814 8682, Fax +55 31 3227 5555, Email acssilva@ 123456hotmail.com , ana@ 123456medicina.ufmg.br

Article

Publisher ID: vhrm-4-0787

DOI: 10.2147/VHRM.S1905

PMC ID: 2597759

PubMed ID: 19065996

SO-VID: 472f0aa3-8c87-4447-808a-a164d48aa40a

Copyright © © 2008 Ribeiro Oliveira et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

The renin–angiotensin system and diabetes: An update

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Karger: Cardiovascular System

Most cited references 150

The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.

International union of pharmacology. XXIII. The angiotensin II receptors.

Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes.

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