Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Primary aldosteronism is one of the most common causes of secondary hypertension. In recent years the prevalence has risen dramatically, from 1% to 14% of all hypertensive patients. This has been largely attributed to an increase in diagnosis. Primary aldosteronism is characterized by hypertension with or without hypokalemia and a high plasma aldosterone concentration (PAC) with a concurrent low plasma renin activity (PRA). The most common subtypes of primary aldosteronism are aldosterone-producing adenoma (42%) and bilateral idiopathic hyperaldosteronism (58%). Other less common subtypes (<1%) are glucocorticoid-remediable aldosteronism, and unilateral primary hyperplasia. Current treatment for primary aldosteronism relies on accurate subtype distinction and assessment of unilateral versus bilateral disease. Bilateral idiopathic hyperaldosteronism is best managed pharmacologically and improves with the use of aldosterone receptor antagonists. Combined treatment with sodium-channel blockers and calcium-channel blockers has also shown satisfactory results. Glucocorticoid-remediable aldosteronism responds well to treatment with low-dose glucocorticoids. Aldosterone producing adenoma and unilateral adrenal hyperplasia are appropriately treated with laparoscopic adrenalectomy. Following adrenalectomy blood pressure improves in 98% of these patients, but only about 33% require no further antihypertensive medication. Identifying the subgroups that will most benefit from adrenalectomy is paramount to formulating individual treatment strategies. In the past, treatment focused mainly on the correction of hypertension and electrolyte disturbances. Now, with accumulating evidence of the detrimental effects of aldosterone to the myocardium, vascular endothelium and kidneys, treatment also focuses on normalizing aldosterone levels or blocking aldosterone action at the receptor level. Therefore, it is essential to accurately identify the specific subtype of primary aldosteronism in order to select optimal treatment and to achieve successful patient outcomes.
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PMID:Prediction of successful outcome in patients with primary aldosteronism. 1805 76

Inflammation is a complex process that reflects the local and systemic responses to different immunological and non-immunological stimuli, enable resistance to disease, repair of tissue damage, and restoration of normal function with the least possible tissue damage. This is achieved by intact regulatory immune system, which includes pro- and anti-inflammatory cytokines, chemokines, growth factors, complement cascade system, renin-angiotensin system, and different sets of adhesion molecules expressed on leukocytes and vascular endothelium, in addition to neutrophils, monocytes/macrophages, and different subsets of T-lymphocytes. Once imbalance occurs in the different factors of the inflammatory response to injurious stimuli, inflammation will proceed and exacerbate tissue damage. Inflammation can be initiated by different stimuli such as deposition or formation of antibody-antigen immune complexes, sensitized T-cells, trauma, tissue necrosis, or infection. It is characterized by activation of acute phase response and release of reactants/markers such as C-reactive protein. Renal inflammation can occur either as an isolated local acute inflammatory reaction or as part of a systemic inflammatory disorder. Recently, there have been tremendous advancements in the fields of immunology and molecular biology that helped in exploring the mechanisms of renal inflammation. This has been accompanied by extensive in vitro and in vivo studies that led to a better understanding of phenotypic changes and multifunctional potentials of local and infiltrating cells, role and control of different inflammatory mediators, adhesion molecules, and the rennin-angiotensin system within the site of inflammation. These achievements helped in researching into ways to modulate renal inflammation, control the severity of renal injury, promote regeneration and tissue repair, and induce tolerance.
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PMID:Modulation of renal inflammation: therapeutic strategies. 1808 17

The renin-angiotensin system (RAS), in particular angiotensin II, plays an important role in cardiac remodelling. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are key players in the RAS and act antagonistically to regulate the levels of angiotensin II. In this study, we reveal the functional expression of ACE2 in human cardiac myofibroblasts, cells that are essential to the maintenance of normal cardiac architecture and also play a key role in myocardial remodelling. The observed reciprocal expression of ACE and ACE2 in these cells may reflect the possible opposing activity of these two enzymes. In this study, we demonstrate the presence of ACE2 as an ectoenzyme and reveal that ACE2 undergoes phorbol-12-myristate-13-acetate-inducible ectodomain shedding from the membrane. When cells were exposed to a number of pathophysiological stimuli, modulation of ACE2 levels was not detected. Importantly, whilst we found ACE2 to be expressed constitutively in cardiac myofibroblasts there were no detectable levels in either vascular smooth muscle cells or vascular endothelium, indicating that ACE2 expression is not ubiquitous. In paraffin sections of atrial appendage tissue, we observed a distinct staining pattern for ACE2 which appeared different from that of ACE. In conclusion, this study is the first to report co-expression of ACE and ACE2 in human cardiac myofibroblasts and may therefore present a model primary system for study of the comparative cell biology of ACE2 and ACE and their potentially opposing roles in myocardial remodelling.
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PMID:Functional angiotensin-converting enzyme 2 is expressed in human cardiac myofibroblasts. 1822 28

In patients with obstructive sleep apnea (OSA), nocturnal exposure to intermittent hypoxia causes elevations in arterial pressure that persist throughout the day. Animal models have shown that this hypertensive effect requires an intact sympathetic nervous system and an intact carotid chemoreceptor reflex. The renin-angiotensin system contributes importantly to hypertension in this model, because renal nerve denervation, angiotensin II receptor blockade, and suppression of the renin-angiotensin system by high salt diet all prevent the rise in blood pressure. The vascular endothelium is functionally impaired in this model and also in patients with OSA. These individuals demonstrate decreased plasma levels of nitric oxide metabolites, increased production of superoxide by neutrophils, and increased levels of 8-isoprostane in breath condensate. Increased levels of pro-inflammatory cytokines are also present. Thus, oxidant stress and inflammation are potential mediators of intermittent hypoxia-induced vascular dysfunction. Once the mechanisms of intermittent hypoxia-induced alterations in vascular structure and function are understood, strategies can be developed to reverse or prevent them. Such research has relevance not only to hypertension, but also to atherosclerosis and other important cardiovascular sequelae of OSA.
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PMID:Vascular consequences of intermittent hypoxia. 1826 89

Hypertension is a major cardiovascular risk factor but most patients remain asymptomatic for many years. Successful therapy not only needs to be effective, it also needs to be well tolerated. beta-blockers are well established as effective antihypertensive agents. However, one major drawback to the currently available beta-blockers, particularly the noncardioselective beta-blockers, is their side-effect profile, including sexual dysfunction, fatigue, depression and metabolic abnormalities such as impaired glucose tolerance and lipid abnormalities. Nebivolol (Bystolic), a novel, highly cardioselective, third-generation beta-blocker that recently received approval by the US FDA for the treatment of hypertension in the USA, is effective in treating blood pressure and has a favorable side-effect profile. Studies conducted in Europe, where nebivolol has been available for some time for the treatment of hypertension, have shown that nebivolol achieves blood pressure reductions comparable to other beta-blockers but with fewer side effects. Additionally, nebivolol has demonstrated similar efficacy in blood pressure reduction when compared with calcium channel blockers and inhibitors of the renin-angiotensin system. When combined with hydrochlorothiazide there was an additive antihypertensive effect. Lastly, nebivolol exhibits a vasodilatory property that is related to its effect on nitric oxide, an intrinsic vasodilator produced in the vascular endothelium. Nebivolol enhances nitric oxide bioavailability. Studies have also demonstrated nebivolol's ability to function as an antioxidant and decrease markers of oxidative stress. These effects are believed to ultimately produce a modulation of the endothelial dysfunction typically seen in hypertension.
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PMID:Beta-blockers in the management of hypertension: focus on nebivolol. 1840 37

Endothelin is a potent and long-acting vasoconstrictor first isolated from the vascular endothelium. It was found in the search for the long-postulated endothelial vascular smooth muscle activator. Recent reports, however, suggest that endothelin may affect the release of the pituitary hormones and control the levels of atrial natriuretic peptide, renin, and the catecholamines. Its widespread distribution within the CNS and other tissues suggests that endothelin may have an important function as a neurotransmitter.
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PMID:Endothelin an endocrine role. 1840 94

Reduction of alveolar PO(2) (alveolar hypoxia, AH) may occur in pulmonary diseases such as chronic obstructive pulmonary disease (COPD), or in healthy individuals ascending to altitude. Altitude illnesses may develop in non-acclimatized persons who ascend rapidly. The mechanisms underlying these illnesses are not well understood, and systemic inflammation has been suggested as a possible contributor. Similarly, there is evidence of systemic inflammation in the systemic alterations present in COPD patients, although its role as a causative factor is not clear.We have observed that AH, induced by breathing 10% O(2) produces a rapid (minutes) and widespread micro vascular inflammation in rats and mice. This inflammation has been observed directly in the mesenteric, skeletal muscle, and pial microcirculations. The inflammation is characterized by mast cell degranulation, generation of reactive O(2) species, reduced nitric oxide levels, increased leukocyte-endothelial adherence in post-capillary venules, and extravasation of albumin. Activated mast cells stimulate the renin-angiotensin system (RAS) which leads to the inflammatory response via activation of NADPH oxidase. If the animals remain in hypoxia for several days, the inflammation resolves and exposure to lower PO(2) does not elicit further inflammation, suggesting that the vascular endothelium has "acclimatized" to hypoxia.Recent experiments in cremaster microcirculation suggest that the initial trigger of the inflammation is not the reduced tissue PO(2), but rather an intermediary released by alveolar macrophages into the circulation. The putative intermediary activates mast cells, which, in turn, stimulate the local renin-angiotensin system and induce inflammation.
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PMID:Alveolar hypoxia-induced systemic inflammation: what low PO(2) does and does not do. 2020 67

Insulinoresistance (IR) and endothelial dysfunction (ED) take part in forming cardiovascular complications. Hyperglycemia, dyslipidemia, and compensatory hyperinsulinemia are triggering factors in the development of ED in diabetes mellitus. Hyperactivation of the renin--angiotensin--aldosterone system and increasing influence of the sympathoadrenal system play an important role in the appearance of ED, which is characterized by a decrease in the synthesis of nitric oxide and an increase in the production of vasoconstrictors. At present, drugs used for ED correction only indirectly influence the functioning of endothelial cells. Eight pharmacological groups including more than 30 drugs are reviewed, which are capable of improving the endothelial function. Progress in the pharmacotherapy of ED stimulates the development of approaches to the individual choice of drugs and the directed correction of the functional state of vascular endothelium.
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PMID:[Endothelial dysfunction in diabetes mellitus and possible ways of pharmacological correction]. 2036 1

Milk-based drinks containing casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to possess antihypertensive and vascular endothelium-protecting properties in hypertensive animal models. Furthermore in clinical intervention trials they reduce blood pressure and arterial stiffness. The exact mechanisms are not known, but inhibition of angiotensin converting enzyme 1 (ACE1) has been suggested mainly to mediate these beneficial effects. The present study investigated the in vitro effects of three tripeptides: Ile-Pro-Pro, Val-Pro-Pro and leqcine-proline-proline (Leu-Pro-Pro) on four renin-angiotensin system enzymes: ACE1, ACE2, chymase, and cathepsin G. Also their effects on arginase I, a critical enzyme in L-arginine-nitric oxide pathway, were studied. It was shown, apparently for the first time, that the inhibitory effects of Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro on ACE1 at micromolar concentrations are competitive in nature. Therefore the efficacy of inhibition is largely dependent on the amount of substrate present. Inhibition of ACE2 and arginase I was reached only at concentrations three orders of magnitude greater. No inhibition of chymase and cathepsin G was observed by the tripeptides. The findings support the hypothesis that Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro act favourably on blood pressure mainly by selective inhibition of ACE1.
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PMID:Effects of milk casein-derived tripeptides Ile-Pro-Pro, Val-Pro-Pro, and Leu-Pro-Pro on enzymes processing vasoactive precursors in vitro. 2048 67

Chronic kidney disease (CKD) is characterized by irreversible pathological processes that result in the development of end-stage renal disease (ESRD). Accumulating evidence has emphasized the important role of chronic hypoxia in the tubulointerstitium in the final common pathway that leads to development of ESRD. The causes of chronic hypoxia in the tubulointerstitium are multifactorial and include mechanisms such as hemodynamic changes and disturbed oxygen metabolism of resident kidney cells. Epidemiological studies have revealed an association between CKD and systemically hypoxic conditions, such as chronic obstructive pulmonary disease and sleep apnea syndrome. In addition to tubulointerstitial hypoxia, glomerular hypoxia can occur and is a crucial factor in the development of glomerular disorders. Chemical compounds, polarographic sensors, and radiographical methods can be used to detect hypoxia. Therapeutic approaches that target chronic hypoxia in the kidney should be effective against a broad range of kidney diseases. Amelioration of hypoxia is one mechanism of inhibiting the renin-angiotensin system, the current gold standard of CKD therapy. Future therapeutic approaches include protection of the vascular endothelium and appropriate activation of hypoxia-inducible factor, a key transcription factor involved in adaptive responses against hypoxia.
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PMID:The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. 2087 4


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