The renin–angiotensin system and diabetes: An update

Figures & data

Figure 1 Novel components of the renin–angiotensin system and its interactions.

Abbreviations: Ang, angiotensin, AT₁, AT₂, angiotensinergic receptors types 1 and 2; NO, nitric oxide; ACE, angiotensin converting enzyme; ACE2, angiotensin-converting enzyme 2.

Table 1 Summary of recent basic research on renin–angiotensin system

Author	Results/Interpretations
Abdalla et al 2000	AT1receptor and the bradykinin (B2) receptor also communicate directly with each other.
Albiston et al 2001	The AT(4) receptor is insulin-regulated aminopeptidase and possibly the AT(4) receptor ligands may exert their effects by inhibiting the catalytic activity of insulin-regulated aminopeptidase.
Baker et al 2004	Losartan did not block the growth effects of Ang II, excluding the involvement of extracellular Ang II and the plasma membrane AT1 receptor. These data demonstrate a previously unknown growth mechanism of Ang II in the heart.
Benter et al 2008	Ang-(1–7) decreased the elevated levels of renal NADPH oxidase (NOX) activity and attenuated the activation of NOX-4 gene expression in the diabetic SHR kidney.
Clark et al 2008	c-Jun N-terminal kinase mediates Ang II-specific astrocyte proliferation.
Donoghue et al 2000	This study identifies ACE2 as the first known human homologue of ACE, an enzyme that plays a central role in vascular, renal, and myocardial physiology. In contrast to ACE, however, ACE2 is highly tissue-specific: whereas ACE is expressed ubiquitously in the vasculature, human ACE2 is restricted to heart, kidney, and testis.
Ferrario et al 2004	Lisinopril augmented plasma levels and urinary excretion rates of Ang I and Ang-(1–7), while plasma Ang II was reduced with no effect on urinary Ang II. Losartan produced similar changes in plasma and urinary Ang-(1–7) but increased plasma Ang II without changing urinary Ang II excretion. This study revealed a role for ACE2 in Ang-(1–7) formation from Ang II in the kidney of normotensive rats as primarily reflected by the increased ACE2 activity measured in renal membranes from the kidney of rats given either lisinopril or losartan.
Fraga-Silva et al 2008	This study is the first to show the presence of Mas protein and specific binding for Ang-(1–7) in rat and mouse platelets. It also suggests that the Ang-(1–7) antithrombotic effect involves Mas-mediated NO release from platelets.
Furuhashi et al 2004	RAS blockade decreases adipocyte size in rats without change in epididymal %fat pads accompanied by improvement in insulin sensitivity.
Gallagher et al 2004	The results of this study suggest that Ang-(1–7) inhibits lung cancer cell growth through the activation of an angiotensin peptide receptor and may represent a novel chemotherapeutic and chemopreventive treatment for lung cancer.
Herath et al 2007	RAS activation in chronic liver injury was shown to be associated with upregulation of ACE2, Mas and hepatic conversion of angiotensin II to angiotensin-(1–7) leading to increased circulatting angiotensin-(1–7).
Jackman et al 2002	The two derivatives of Ang I, Ang 1–9, and Ang 1–7, liberated by enzymes in heart tissues, were shown to enhance the local effects of kinins by augmenting NO and arachidonic acid release.
Jankowski et al 2007	Ang A was shown to be a novel human strong vasoconstrictive angiotensin-derived peptide. Plasma Ang A concentration seems to be increased in end-stage renal failure. Because of its stronger agonism at the AT2 receptor, it is suggested that Ang A may modulate the harmful effects of Ang II.
Kohlstedt et al 2004	ACE was shown to be involved in outside-in signaling in endothelial cells and “ACE signaling” was suggested to be an important cellular mechanism contributing to the beneficial effects of ACE inhibitors
Kostenis et al 2005	This study showed that Mas can hetero-oligomerize with the AT1 receptor and by so doing inhibit the actions of angiotensin II. This is a novel demonstration that a G-protein-coupled receptor acts as a physiological antagonist of a previously characterized receptor.
Lau et al 2004	The data coming from this study indicate the existence of an islet angiotensin-generating system of potential importance in the physiological regulation of glucose induced insulin secretion, thus diabetes mellitus.
Lupi et al 2006	RAS molecules were shown in human islets and their expression was sensitive to glucose concentration. ACE inhibitors, and in particular zofenoprilat, protected human islets from glucotoxicity and the effects of ACE inhibition were associated with decreased oxidative stress.
Maia et al 2004	This study suggests that endogenous Ang-(1–7) and/or an Ang-(1–7)-related peptide plays an important role in the BK potentiation by ACEI through a mechanism not dependent upon inhibition of ACE hydrolytic activity.
Nagata et al 2006	The identification of proangiotensin-12 suggests a processing cascade of the RA system, different from the cleavage of angiotensinogen to Ang I by renin.
Nguyen et al 2002	This study highlights the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II.
Paizis et al 2005	ACE2 expression is significantly increased in liver injury in both humans and rat, and may modulate RAS activity in cirrhosis.
Pereira et al 2007	This study showed in a model of hepatic fibrosis the RAS activation. It also suggested that Ang-(1–7) played a protective role in hepatic fibrosis.
Sampaio et al 2007a	This study demonstrated that, in human endothelial cells, Ang-(1–7) negatively modulates Ang II/Ang II type1 receptor-activated c-Src and its downstream targets ERK1/2 and NAD(P)H oxidase. They also show that SHP-2-c-Src interaction is enhanced by Ang-(1–7).
Sampaio et al 2007b	They demonstrated that Ang-(1–7), through Mas, stimulates eNOS activation and NO production via Akt- dependent pathways.
Santos et al 2008	The result from this study showed that Mas deficiency in FVB/N mice leads to dramatic changes in glucose and lipid metabolisms, inducing a metabolic syndrome-like state.
Sarzani et al 2008	Cell proliferation was progressively stimulated by increasing Ang II concentrations and inhibited by atrial natriuretic pepetide in both visceral mature adipocytes and in vitro differentiated preadipocytes. Co-incubation with increasing Ang II concentrations and valsartan indicated that Ang II effects were AT1-mediated.
Tallant et al 2005	The use of transfection of cultured myocytes with an antisense oligonucleotide to the mas receptor blocked in this model the ANG-(1–7)-mediated inhibition of serum-stimulated MAPK activation, whereas a sense oligonucleotide was ineffective. These results suggested that ANG-(1–7) reduced the growth of cardiomyocytes through activation of the mas receptor.
Tikellis et al 2003	This study showed by immunostaining that both ACE2 and ACE protein were localized predominantly to renal tubules. In the diabetic kidney, there was reduced ACE2 protein expression that was prevented by ACE inhibitor therapy.
Vincent et al 2003	This study concludes that insulin specifically recruits flow to the microvasculture in skeletal muscle via a nitric oxide dependent pathway and that this may be important to insulin’s overall action to regulate glucose disposal.
Zisman et al 2003	This study showed that Ang-(1–7)-forming activity from both Ang I and Ang II was increased in failing human heart ventricles but it was mediated by at least two different angiotensinases. The first, which demonstrated substrate preference for Ang I, was neutral endopeptidase-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C16.

Table 2 Summary of recent clinical research on renin–angiotensin system

Author	Results/Interpretations
Bojestig et al 2000	PRA and Ang II concentrations were significantly lower in diabetic patients than in the controls. The levels of atrial natriuretic peptide, on the other hand, were higher in patients than in controls. PRA correlated negatively to the mean value of HbA(1c) during the previous five years.
Brenner et al 2001 for the RENAAL Study	Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25%; P = 0.006) and end-stage renal disease (risk reduction, 28%; P = 0.002) but had no effect on the rate of death. Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy.
Dahlof et al 2002	Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefits beyond reduction in blood pressure, and new onset diabetes was less frequent with losartan.
Gross et al 2007	The survey of specific functional polymorphisms of the RAS, namely the angiotensin-I-converting enzyme (ACE) D/I, the angiotensinogen (AGT) T174M and M235T, and A1166C of the angiotensin-II receptor 1 (AGTR1), revealed that the incidence recurrent instent restenosis in a high risk cohort was not associated with any of the polymorphisms examined in this study.
Gumprecht et al 2000	The results of this study suggest that ACE gene insertion/deletion and angiotensinogen M235T polymorphisms contribute to the increased risk for the development of chronic renal failure,
HOPE 2000	Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was shown to be greater than that attributable to the decrease in blood pressure.
Lieb et al 2006	This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, septal wall thickness, and left ventricular hypertrophy in hemizygous men.
Lewis et al 2001	The angiotensin-II-receptor blocker irbesartan was effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection was independent of the reduction in blood pressure it causes.
Lindholm et al 2002	Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and left ventricular hypertrophy. Losartan seems to have benefits beyond blood pressure reduction.
Matayoshi et al 2007	This study shows that the systemic RAS may modulate insulin sensitivity in essential hypertensive patients.
Merrill et al 2002	This study demonstrates, for the first time, increased plasma Ang-(1–7) in normal pregnant subjects compared with nonpregnant subjects and decreased Ang-(1–7) in preeclamptic subjects compared with normal pregnant subjects.
Mukai et al 2002	The results of this study demonstrate that long-term inhibition of the renin-angiotensin system of COX-2-derived vasoconstricting factors and superoxide anions.
Nogueira et al 2007	This study suggests that reduced levels of the vasodilator Ang-(1–7) could be implicated in the endothelial dysfunction seen in gestational diabetic women during and after pregnancy.
Parving et al 2001	This study showed that Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria
Simões e Silva et al 2006b	This study showed different circulating RAS profiles between hypertensive and in normotensive chronic renal failure subjects. Marked changes in plasma Ang-(1–7) were associated with the presence of hypertension and progression of kidney dysfunction.
Simões e Silva et al 2004	This study showed different RAS profiles in childhood hypertension and suggested a blood pressure-independent change of Ang-(1–7) in essential hypertension.
Wijpkema et al 2006	In this study, the authors could establish a role for the AT1R 1166A/C polymorphism in restenosis after percutaneous coronary intervention. However, significant gene – gene interaction was suggested for the ACE gene and the HO-1 promotor, meriting further investigation in restenosis.
Winkelmann et al 1999	The significant relations observed in this study between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating angiotensinogen in the pathogenesis of coronary artery disease.
Yang et al 2007	The results of this study indicate that common genetic variants in the ACE2 gene might impact on myocardial infarction in females, and may possibly interact with alcohol consumption to affect the risk of coronary heart disease and myocardial infarction in Chinese males.
Yusuf et al 2001	This study demonstrated that ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals.
Zhong et al 2006	This study concluded that the ACE2 A/G polymorphism is associated with hypertension in patients with metabolic syndrome.
Zisman et al 2003	This study showed that Ang-(1–7)-forming activity from both Ang I and Ang II was increased in failing human heart ventricles but it was mediated by at least two different angiotensinases. The first, which demonstrated substrate preference for Ang I, was neutral endopeptidase-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C16.

Figure 2 Interactions between angiotensin II and insulin receptor in vascular smooth muscle cells.

Abbreviations: Ang II, angiotensin II; MAPK, mitogen-activated protein kinase; PAI 1, plasminogen activator inhibitor-1; MCP 1, monocyte chemoattractant protein 1; ICAM 1, intracellular cell adhesion molecule-1; PI3K, inositol 3-phosphatidil kinase; eNOS, endothelial nitric oxide synthase.

Figure 3 Interactions between renin–angiotensin system, kinin–kallikrein system, and insulin signaling transduction pathways.

Abbreviations: MAPK, mitogen-activated protein kinase; PI3K, inositol 3 phosphatidil kinase; Ang, Angiotensin; ACE, angiotensin-converting enzyme; ACE2, angiotensin-convert-ing enzyme 2; AT₁, AT₂, angiotensinergic receptors types 1 and 2; Mas, Mas receptor of angiotensin-(1–7); NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; ET1, endothelin 1; TXA₂, thromboxane A₂; PAI 1, plasminogen activator inhibitor; VCMS, vascular smooth muscle cell; ICAM1, intracellular adhesion molecule 1.

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