Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 a cascade of enzymatic reactions resulting ultimately in the formation of angiotensin II. Recent research has expanded the knowledge about the RAS by adding new components to the pathways: angiotensin-(1-5) [Ang-1-5], angiotensin-(1-7) [Ang-(1-7)], angiotensin-(1-9) [Ang-(1-9)], an ACE homologous enzyme, ACE2, and the G-protein-coupled receptor mas as a molecular receptor for Ang-(1-7). Although previous studies provided some conflicting evidence about the relevance of Ang-(1-7) in the regulation of vascular and renal function, data now demonstrate that Ang-(1-7) contributes to the cardiovascular effects of ACE-inhibitors (ACE-1) and AT1-receptor-blockers (ARBs) both in experimental conditions and in humans. This review summarizes and critically discusses the currently available experimental and clinical study evidence for the role of Ang-(1-7) as a vasodilator and anti-trophic peptide in cardiovascular drug therapy. In addition, the potential therapeutic impact of currently available RAS blocking agents (ACE-1 and ARBs) and new agents still under development (renin-inhibitors) on the RAS-effector peptides is highlighted.
 ...
PMID:Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy. 1758 83

There is an increasing body of evidence to suggest that the RAS (renin-angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-beta1, IL (interleukin)-1beta, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1-7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2-angiotensin-(1-7)-Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.
 ...
PMID:Liver fibrosis: a balance of ACEs? 1760 May 27

The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists.
 ...
PMID:An update on non-peptide angiotensin receptor antagonists and related RAAS modulators. 1769 38

Angiotensin converting enzyme (ACE) is a key enzyme in the renin angiotensin system (RAS) and converts angiotensin (Ang) I to the vasoconstrictor Ang II, which is thought to be responsible for most of the physiological and pathophysiological effects of the RAS. This classical view of the RAS was challenged with the discovery of the enzyme, ACE2 which both degrades Ang II and leads to formation of the vasodilatory and anti-proliferative peptide, Ang 1-7. Activation of the RAS is a major contributor to diabetic complications, and blockade of the vasoconstrictor and hypertrophic actions of Ang II, slows but does not prevent the progression of such complications. The identification of ACE2 in the heart and kidney adds further complexity to the RAS, provides the rationale to explore the role of this enzyme in pathophysiological states, including the microvascular and macrovascular complications of diabetes. It is believed that ACE2 acts in a counter-regulatory manner to ACE to modulate the balance between vasoconstrictors and vasodilators within the heart and kidney, and may thus play a significant role in the pathophysiology of cardiac and renal disease. Relatively little is known about ACE2 in diabetes, and this review will explore and discuss the data that is currently available. The discovery of ACE2 presents a novel opportunity to develop drugs that specifically influence ACE2 activity and/or expression, and it is possible that such compounds may have considerable clinical value in the prevention and treatment of the complications of diabetes.
 ...
PMID:ACE2 and diabetic complications. 1789 17

Components of the renin-angiotensin system are well established targets for pharmacological intervention in a variety of disorders. Many such therapies abrogate the effects of the hypertensive and mitogenic peptide, angiotensin II, by antagonising its interaction with its receptor, or by inhibiting its formative enzyme, angiotensin-converting enzyme (ACE). At the turn of the millennium, a homologous enzyme, termed ACE2, was identified which increasingly shares the limelight with its better-known homologue. In common with ACE, ACE2 is a type I transmembrane metallopeptidase; however, unlike ACE, ACE2 functions as a carboxypeptidase, cleaving a single C-terminal residue from a distinct range of substrates. One such substrate is angiotensin II, which is hydrolysed by ACE2 to the vasodilatory peptide angiotensin 1-7. In this commentary we discuss the latest developments in the rapidly progressing study of the physiological and patho-physiological roles of ACE2 allied with an overview of the current understanding of its molecular and cell biology. We also discuss parallel developments in the study of collectrin, a catalytically inactive homologue of ACE2 with critical functions in the pancreas and kidney.
 ...
PMID:Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. 1789 33

A recently discovered homologue of the angiotensin-converting enzyme, ACE2, insensitive to ACE inhibitors, was found in rodents and humans. ACE2 is expressed mainly in the vasculature, heart and kidney. ACE2 removes a single amino acid of the carboxy terminal of peptides. In the renin-angiotensin-aldosterone system (RAAS), it is responsible for the conversion of angiotensin I (Ang I) and angiotensin II (Ang II) to Ang 1-9 and Ang 1-7, respectively. While ACE forms Ang II, a potent vasoconstrictor, ACE2 degrades this peptide to form Ang 1-7 which has an opposite action. Therefore, ACE2 counteracts ACE in the balance of vasopressor/vasodilator as well as heart and kidney function. The importance of ACE2 in physiological and pathophysiological conditions is unclear and is currently being studied.
 ...
PMID:[The importance of ACE2 in regulating the cardiovascular system]. 1796 9

Angiotensin-converting enzyme (ACE) 2 is thought to counterbalance ACE by breakdown of angiotensin (Ang) II and formation of Ang(1-7). Both enzymes are highly expressed in the kidney, but reports on their regulation differ. To enhance our understanding of the regulation of renal ACE and ACE2, we investigated renal ACE and ACE2 expression during conditions of physiological (low-sodium diet) and pharmacological changes (ACE inhibition) in activity of the renin-angiotensin-aldosterone system (RAAS). Healthy rats were treated with vehicle or lisinopril with either a control or a low-sodium diet, and renal ACE2, ACE and plasma angiotensins were studied. During vehicle treatment, low sodium reduced renal ACE mRNA and activity without affecting ACE2 mRNA or activity and plasma Ang(1-7) and Ang II balance. Lisinopril significantly reduced renal ACE activity without affecting renal ACE2 activity. During ACE inhibition, low sodium reduced both ACE and ACE2 mRNA without affecting ACE2 activity or further reducing ACE activity. Measurements of renal neprilysin activity revealed no significant differences between any of the treatment groups. Plasma Ang(1-7) and Ang II balance is positively shifted towards the beneficial vasopeptide Ang(1-7) by the ACE inhibitor lisinopril, especially during a low sodium intake. In conclusion, modulation of the RAAS, by low sodium intake or ACE inhibition, does not affect renal ACE2 despite major variations in renal ACE. Thus, ACE and ACE2 are differentially regulated by low sodium and ACE inhibition. Therefore, we propose that the beneficial effects of ACE inhibitors are predominantly mediated by modulation of ACE and not ACE2. Whether this also applies to renal disease conditions should be investigated in future studies.
 ...
PMID:Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats. 1819 34

Angiotensin-converting enzyme (ACE) and ACE2 and the AT1 and AT2 receptors are pivotal points of regulation in the renin-angiotensin system. ACE and ACE2 are key enzymes in the formation and degradation of angiotensin II (Ang II) and angiotensin-(1-7)(Ang-(1-7)). Ang II acts at either the AT1 or the AT2 receptor to mediate opposing actions of vasoconstriction or vasodilatation respectively. While it is known that oestrogen acts to downregulate ACE and the AT(1) receptor, its regulation of ACE2 and the AT2 receptor and the involvement of a specific oestrogen receptor subtype are unknown. To investigate the role of oestrogen receptor-alpha (ERalpha) in the regulation by oestrogen of ACE/ACE2 and AT1/AT2 mRNAs in lung and kidney, ovariectomized female mice lacking apolipoprotein E (ee) with the ERalpha (AAee) or without the ERalpha (alphaalphaee) were treated with 17beta-oestradiol (6 microg day(-1)) or placebo for 3 months. ACE, ACE2, AT1 receptor and AT2 receptor mRNAs were measured using reverse transcriptase, real-time polymerase chain reaction. In the kidney, 17beta-oestradiol showed 1.7-fold downregulation of ACE mRNA in AAee mice, with 2.1-fold upregulation of ACE mRNA in alphaalphaee mice. 17beta-Oestradiol showed 1.5- and 1.8-fold downregulation of ACE2 and AT1 receptor mRNA in AAee mice; this regulation was lost in alphaalphaee mice. 17beta-Oestradiol showed marked (81-fold) upregulation of the AT(2) receptor mRNA in AAee mice. In the lung, 17beta-oestradiol treatment had no effect on AT1 receptor mRNA in AAee mice, but resulted in a 1.5-fold decreased regulation of AT1 mRNA in alphaalphaee mice. There was no significant interaction of oestrogen with ERalpha in the lung for ACE, ACE2 and AT2 receptor genes. These studies reveal tissue-specific regulation by 17beta-oestradiol of ACE/ACE2 and AT1/AT2 receptor genes, with the ERalpha receptor being primarily responsible for the regulation of kidney ACE2, AT1 receptor and AT2 receptor genes.
 ...
PMID:Tissue-specific regulation of ACE/ACE2 and AT1/AT2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor-alpha knock-out mice. 1819 35

We recently reported the presence of angiotensin-converting enzyme (ACE)2 in brain regions controlling cardiovascular function; however, the role of ACE2 in blood pressure regulation remains unclear because of the lack of specific tools to investigate its function. We hypothesized that ACE2 could play a pivotal role in the central regulation of cardiovascular function by regulating other renin-angiotensin system components. To test this hypothesis, we generated an adenovirus expressing the human ACE2 cDNA upstream of an enhanced green fluorescent protein (eGFP) reporter gene (Ad-hACE2-eGFP). In vitro characterization shows that neuronal cells infected with Ad-hACE2-eGFP (10 to 100 multiplicities of infection), but not Ad-eGFP (100 multiplicities of infection), exhibit dose-dependent ACE2 expression and activity. In addition, an active secreted form was detected in the conditioned medium. In vivo, Ad-hACE2-eGFP infection (2x10(6) plaque-forming units intracerebroventricularly) produced time-dependent expression and activity (with a peak at 7 days) in the mouse subfornical organ. More importantly, 7 days after virus infection, the pressor response to angiotensin (Ang) II (200 pmol intracerebroventricularly) was significantly reduced in Ad-hACE2-eGFP-treated mice compared with controls. Furthermore, subfornical organ-targeted ACE2 overexpression dramatically reduced the Ang II-mediated drinking response. Interestingly, ACE2 overexpression was associated with downregulation of the Ang II type 1 receptor expression both in vitro and in vivo. These data suggest that ACE2 overexpression in the subfornical organ impairs Ang II-mediated pressor and drinking responses at least by inhibiting the Ang II type 1 receptor expression. Taken together, our results show that ACE2 plays a pivotal role in the central regulation of blood pressure and volume homeostasis, offering a new target for the treatment of hypertension and other cardiovascular diseases.
 ...
PMID:Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation. 1836 60

The chorionic villi in the placenta are responsible for the regulation of fetal oxygen and nutrient transport. Although the peripheral renin-angiotensin system is activated during normal pregnancy, the regulation of the local chorionic villi renin-angiotensin system remains unknown. Therefore, placental chorionic villous tissue was collected from nulliparous third-trimester normotensive or preeclamptic subjects and was analyzed for angiotensin peptide content, angiotensinogen, renin, angiotensin-converting enzyme (ACE), ACE2, neprilysin, angiotensin II type 1 (AT(1)), angiotensin II type 2, Mas receptor mRNAs, and angiotensin receptor density and subtype. Angiotensin II in chorionic villi was significantly higher in preeclamptic subjects, whereas angiotensin (1-7) was not different. Angiotensinogen and AT(1) receptor gene expression was significantly higher in preeclamptic subjects. No differences were observed in renin, ACE, ACE2, or neprilysin gene expression. Mas receptor mRNA in preeclamptic subjects was decreased. The AT(1) receptor was the predominant receptor subtype in normal and preeclamptic chorionic villi. There was no difference in the density of the AT(1,) angiotensin II type 2, and angiotensin (1-7) receptors. These results indicate that enhanced chorionic villous expression of angiotensin II may result from increased angiotensinogen. Elevated angiotensin II, acting through the AT(1) receptor, may favor vasoconstriction in placental chorionic villi and contribute to impaired fetal blood flow and decreased fetal nutrition observed during preeclampsia.
 ...
PMID:Activation of local chorionic villi angiotensin II levels but not angiotensin (1-7) in preeclampsia. 1825 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>