Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) is involved in the pathological mechanisms of target organ damage, as well as in the induction of hypertension. RAS inhibition by angiotensin converting enzyme (ACE) inhibitors and angiotensin (Ang) II receptor blockers can prevent tissue damage by inhibition of Ang II type 1 receptor signaling. A beneficial effect of RAS inhibition on the heart, vasculature and kidney in cardiovascular disease has been reported. However, RAS inhibition can also prevent fibroproliferative diseases and damage of other tissues, such as brain, adipose tissue and muscle, because local RAS has an important role in tissue damage compared with circulating RAS. Moreover, other players, such as Ang II type 2 receptor signaling, aldosterone and ACE2 have been highlighted. Furthermore, there has also been a focus on the emerging concept of regulation of RAS, such as receptor-interacting proteins and receptor modifications, in the new discovery of therapeutic agents for tissue protection. The RAS has a pivotal role in various target organ damage, with complicated mechanisms; therefore, blockade of RAS may be therapeutically effective in preventing organ damage, as well as in having an antihypertensive effect.
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PMID:Inhibition of the renin-angiotensin system and target organ protection. 1926 96

Fifty years since their introduction, thiazide diuretics are established as first-line therapy in the treatment of hypertension. Because the dosing profile for thiazide agents lessened, the mechanism responsible for the blood pressure lowering effect may lie outside their diuretic properties. We evaluated the mechanism driving blood pressure reductions in spontaneously hypertensive rats (SHR) and normotensive WKY by examining the effects of low-dose hydrochlorothiazide (HCTZ) administration on renin-angiotensin system (RAS) components. The 7-day, 1.5 mg/kg/day HCTZ did not change systolic pressure in WKY, but decreased SBP by 41 +/- 2 mm Hg (p < 0.0001) in SHR. This reduction was independent of increases in water intake, urine output, or alterations in electrolyte excretion. HCTZ significantly increased the plasma concentrations of angiotensin I (Ang I) and angiotensin II (Ang II) in both WKY and SHR while reducing angiotensin converting enzyme (ACE) activity and the Ang II/Ang I ratio (17.1 +/- 2.9 before versus 10.3 +/- 2.9 after, p < 0.05) only in SHR. HCTZ increased cardiac ACE2 mRNA and activity, and neprilysin mRNA in WKY, but not SHR. Conversely in SHR, ACE2 activity was decreased and aside from a 75% increase in AT(1) mRNA in the HCTZ-treated SHR, the expression of the other variables remained unaltered. Measures of cardiac mas receptor mRNA showed no changes in response to treatment in both strains, although cardiac mas mRNA was significantly lower in untreated SHR. These data, which document for the first time the effect of low-dose thiazide on the activity of the ACE2/Ang-(1-7)/mas-receptor axis, suggest that the opposing arm of the system does not substantially contribute to the antihypertensive effect of low-dose thiazides in SHR.
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PMID:Differential effect of low dose thiazides on the Renin Angiotensin system in genetically hypertensive and normotensive rats. 1934 87

Ang-(1-7) (angiotensin-1-7), a peptide product of the recently described ACE (angiotensin-converting enzyme) homologue ACE2, opposes the harmful actions of AngII (angiotensin II) in cardiovascular tissues, but its role in liver disease is unknown. The aim of the present study was to assess plasma levels of Ang-(1-7) in human liver disease and determine its effects in experimental liver fibrosis. Angiotensin peptide levels were measured in cirrhotic and non-cirrhotic patients with hepatitis C. The effects of Ang-(1-7) on experimental fibrosis were determined using the rat BDL (bile-duct ligation) model. Liver histology, hydroxyproline quantification and expression of fibrosis-related genes were assessed. Expression of RAS (renin-angiotensin system) components and the effects of Ang-(1-7) were examined in rat HSCs (hepatic stellate cells). In human patients with cirrhosis, both plasma Ang-(1-7) and AngII concentrations were markedly elevated (P<0.001). Non-cirrhotic patients with hepatitis C had elevated Ang-(1-7) levels compared with controls (P<0.05), but AngII concentrations were not increased. In BDL rats, Ang-(1-7) improved fibrosis stage and collagen Picrosirius Red staining, and reduced hydroxyproline content, together with decreased gene expression of collagen 1A1, alpha-SMA (smooth muscle actin), VEGF (vascular endothelial growth factor), CTGF (connective tissue growth factor), ACE and mas [the Ang-(1-7) receptor]. Cultured HSCs expressed AT1Rs (AngII type 1 receptors) and mas receptors and, when treated with Ang-(1-7) or the mas receptor agonist AVE 0991, produced less alpha-SMA and hydroxyproline, an effect reversed by the mas receptor antagonist A779. In conclusion, Ang-(1-7) is up-regulated in human liver disease and has antifibrotic actions in a rat model of cirrhosis. The ACE2/Ang-(1-7)/mas receptor axis represents a potential target for antifibrotic therapy in humans.
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PMID:Angiotensin-(1-7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat. 1937 Dec 32

The renin angiotensin system (RAS) plays a major role in liver fibrosis. A novel homologue of angiotensin converting enzyme, ACE2, was identified as a negative regulator of RAS as it degrades Ang II to Ang1-7. We investigated in vivo the expression of ACE2 in liver fibrosis. We evaluated the relationship between biochemical variables and liver tissue expression of ACE2, the correlation between a histological assessment of liver fibrosis and liver tissue expression of ACE2. Male SD rats were randomly divided into a CCL4 group which received injections of CCL4 and the control group which received injections of olive oil. Liver pathology was examined by H&E and Sirius red staining, and real-time PCR was performed to determine the gene expression levels of ACE2 and ACE. Real-time PCR analysis revealed that ACE2 mRNA was higher at the two-, four-, and six-week time points, respectively (p<0.01). Similarly, hepatic ACE mRNA was significantly increased after CCL4 injection. There was a significant correlation between ACE and ACE2 gene expression (r=0.750, P<0.001). ACE2 gene expression strongly correlated with ALT (r=0.669, P<0.0001) and AST levels (r=0.815, P<0.0001). There was a significant correlation between circulating ACE2 and histological scores of liver fibrosis. ACE2 and ACE gene expression correlated with the ISHAK score (r=0.850, P<0.001; r=0.806, P<0.001). There was a significant relationship between ACE2 gene expression and the degree of liver fibrosis. ACE2 plays a crucial role in liver fibrogenesis.
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PMID:Expression of angiotensin-converting enzyme 2 in CCL4-induced rat liver fibrosis. 1942 97

Our view of renin-angiotensin system (RAS) has changed over the past two decades: new metabolites and pathways have been described; also the importance of local renin-angiotensin systems became more clearly understood. However, there is relatively scarce information about formation and action of angiotensin peptides in gastrointestinal tract, especially in the stomach. Here, using LC-ESI-MS method we assessed the metabolism of Ang I in organ bath of rat stomach wall. Additionally we compared the expression of mRNA of angiotensin converting enzymes (ACE, ACE2) and neprilysin (NEP) in the stomach, aorta and renal artery in rats. Despite, similar levels of expression of ACE and ACE2 mRNA in stomach wall, aorta and renal artery, the absolute amounts of main Ang I metabolites produced by stomach wall (in ng/mg of dry tissue) were much lower than that produced by aorta and renal artery. Also, the pattern of angiotensin I metabolites was different: opposite to aorta and renal artery, incubation of Ang I with stomach wall fragments resulted in predominant formation of Ang-(1-7) and relatively lower production of Ang II. In stomach wall both, perindoprilat and tiorphan decreased production of Ang II, but did not influence generation of Ang-(1-7). In conclusion, we identified Ang-(1-7) as the main product of Ang I conversion in rat stomach wall. The biological role of prevalence of Ang-(1-7) formation in stomach require further investigation.
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PMID:Angiotensin metabolism in rat stomach wall: prevalence of angiotensin-(1-7) formation. 1943 22

Alterations within the RAS (renin-angiotensin system) are pivotal for the development of renal disease. ACE2 (angiotensin-converting enzyme 2) is expressed in the kidney and converts the vasoconstrictor AngII (angiotensin II) into Ang-(1-7), a peptide with vasodilatory and anti-fibrotic actions. Although the expression of ACE2 in the diabetic kidney has been well studied, little is known about its expression in non-diabetic renal disease. In the present study, we assessed ACE2 in rats with acute kidney injury induced by STNx (subtotal nephrectomy). STNx and Control rats received vehicle or ramipril (1 mg. kg (-1) of body weight . day (-1), and renal ACE, ACE2 and mas receptor gene and protein expression were measured 10 days later. STNx rats were characterized by polyuria, proteinuria, hypertension and elevated plasma ACE2 activity (all P<0.01) and plasma Ang-(1-7) (P<0.05) compared with Control rats. There was increased cortical ACE binding and medullary mas receptor expression (P<0.05), but reduced cortical and medullary ACE2 activity in the remnant kidney (P<0.05 and P<0.001 respectively) compared with Control rats. In STNx rats, ramipril reduced blood pressure (P<0.01), polyuria (P<0.05)and plasma ACE2 (P<0.01), increased plasma Ang-(1-7) (P<0.001), and inhibited renal ACE(P<0.001). Ramipril increased both cortical and medullary ACE2 activity (P<0.01), but reduced medullary mas receptor expression (P<0.05). In conclusion, our results show that ACE2 activity is reduced in kidney injury and that ACE inhibition produced beneficial effects in association with increased renal ACE2 activity. As ACE2 both degrades AngII and generates the vasodilator Ang-(1-7), a decrease in renal ACE2 activity, as observed in the present study, has the potential to contribute to the progression of kidney disease.
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PMID:Reduction in renal ACE2 expression in subtotal nephrectomy in rats is ameliorated with ACE inhibition. 1969 82

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family.
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PMID:Not just angiotensinases: new roles for the angiotensin-converting enzymes. 1976 95

1. The role of angiotensin-converting enzyme (ACE) 2 is likely to balance the status of the renin-angiotensin system (RAS) by degrading angiotensin (Ang) II and generating Ang-(1-7). Earlier demonstrations that ACE2 is insensitive to ACE inhibitors prompted us to evaluate the effect of ACE inhibitors on ACE2 expression. 2. Liver fibrosis was induced in rats with 40% CCl(4) (2.5 mL/kg, s.c., twice per week). Half the rats were further treated with perindopril (2 mg/kg, p.o., daily). After 2 and 4 weeks treatment, ACE2 immunoreactivity was assessed by immunohistochemical staining, ACE2 protein expression was determined by western blot and mRNA expression of ACE2 and the Ang-(1-7) receptor Mas was determined by reverse transcription-polymerase chain reaction (RT-PCR). 3. As an in vitro study, hepatic stellate cells (HSC) were treated with AngII (0.1-10 micromol/L) alone or in combination with the synthesized peptide ACEI (Sigma-Aldrich). Western blot and RT-PCR were used to evaluate ACE2 expression and Mas mRNA levels. Furthermore, after treatment of HSC with the Mas antagonist A779 (1 micromol/L), the protein expression of connective tissue growth factor (CTGF) was detected to evaluate the interaction between AngII, ACEI and the ACE2-Mas axis. 4. Expression of both ACE2 mRNA and protein and Mas mRNA was markedly upregulated in both CCl(4)-injured rat liver and AngII-treated HSC. Further significant upregulation was observed following additional administration of ACEI. In addition, ACEI treatment of HSC inhibited AngII-induced overexpression of connective tissue growth factor and this effect was ameliorated by blockade of the Mas receptor with A779. 5. The findings of the present study suggest that ACE inhibitors are able to upregulate ACE2 under conditions of liver injury both in vivo and in vitro, which may indicate potential benefits of ACE inhibitors in the therapeutic treatment of liver fibrosis.
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PMID:Upregulation of angiotensin-converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors. 1979 8

Angiotensin-(1-7), a biologically active peptide of the renin-angiotensin system, is cardioprotective following ischemia/reperfusion and reduces cardiac hypertrophy. A recently discovered homolog of angiotensin converting enzyme (ACE), ACE2, is present in the heart and synthesizes angiotensin-(1-7) from angiotensin II. Cardiac ACE2 is elevated following inhibition of Ang II subtype 1 (AT(1)) receptors or blockade of angiotensin II production, suggesting that angiotensin-(1-7) plays a role in the beneficial effects of AT(1) receptor antagonists and ACE inhibitors in the heart. An increase in ACE2 activity and the production of angiotensin-(1-7) may thus represent a novel therapy for heart failure following myocardial infarction.
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PMID:Cardioprotective role for angiotensin-(1-7) and angiotensin converting enzyme 2 in the heart. 1980 91

A novel angiotensin-converting enzyme (ACE) homolog, named ACE2, was recently described. ACE2 degrades Ang II, a peptide with vasoconstrictive and proliferative effects, to generate Ang-(1-7), which, acting through its receptor Mas, exerts vasodilatory and antiproliferative actions. In addition, ACE2 is a multifunctional enzyme and its actions on other vasoactive peptides can also contribute to its vasoactive effects. The discovery of ACE2 corroborates the establishment of two counter-regulatory arms within the renin-angiotensin system. The first arm is formed by the classical pathway involving the ACE-Ang II-AT(1)-receptor axis, and the second arm is constituted by the ACE2-Ang-(1-7)-Mas-receptor axis. Owing to its characteristics, the ACE2-Ang-(1-7)-Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of hypertension and cardiovascular diseases. In this review, we will summarize the biochemical and pathophysiological aspects of ACE2 with particular focus on its role in the heart.
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PMID:Cardiovascular protection by angiotensin-converting enzyme 2: a new paradigm. 1980 94


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