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 authors analyze the data of histochemical examinations of 30 patients with tumorous and nontumorous forms of low-renin hyperaldosteronism, as well as the findings of clinical and hormonal examinations of these patients. The activities of enzymes involved in steroidogenesis (3-beta OSD, NAD and NADP tetrazolium reductases, G-6-PD) were measured, as were levels and distribution patterns of lipids involved in steroidogenesis (free and bound cholesterol, etc.). A high functional activity of aldosteromas of any structure was proved, and a trend to increase of steroidogenic activity of malignant aldosteromas demonstrated. Atrophic changes in the cortex adjacent to aldosteroma were found to involve no reduction of adrenal tissue functional activity. In contrast to this, hyperplastic changes in the cortex adjacent to adenoma were characterized by a lower level of functional activity as against adrenal tissue activity in nontumorous hyperaldosteronism. The authors come to a conclusion that adrenocortical elements hyperplasia associated with some aldosteromas does not participate in aldosterone hyperproduction whereas hyperaldosteronism in nontumorous variants is caused by cortical cell hyperplasia and hormone hyperproduction.
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PMID:[Histochemical characteristics of aldosteromas and adrenal tissue of patients with primary hyperaldosteronism]. 816 9

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) modulates the access of corticosteroids to their receptors and is important in blood pressure control. The excretion of renal 11 beta-HSD (ie, NAD(+)-dependent isoform) is thought to protect renal mineralocorticoid receptors from cortisol. To examine whether endogenous renal 11 beta-HSD inhibitory factor(s) may be involved in the pathophysiology of hypertension, we studied the urinary excretion of such inhibitors in 30 patients with low-renin essential hypertension and 20 normotensive control subjects. The effect of sodium restriction on the urinary excretion of the inhibitors wa also evaluated in six normotensive control subjects. Urine was extracted with Sep-Pak cartridges and high-performance liquid chromatography. Endogenous renal 11 beta-HSD inhibitors were measured by the inhibition of 11 beta-HSD bioactivity in microsomes from the human kidney. The urinary excretion of the inhibitors was significantly increased in patients with low-renin essential hypertension (1280 +/- 88 nmol/d, mean +/- SEM) compared with normotensive control subjects (704 +/- 56 nmol/d) (P < .05). Ratios of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone did not differ significantly. Sodium restriction reduced the urinary excretion of the endogenous renal 11 beta-HSD inhibitors but did not affect the ratio of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone. Endogenous renal 11 beta-HSD inhibitory factors may contribute to the pathogenesis of low-renin essential hypertension by modulating the activity of 11 beta-HSD. Sodium intake may directly or indirectly regulate the inhibitory factors.
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PMID:Endogenous renal 11 beta-hydroxysteroid dehydrogenase inhibitory factors in patients with low-renin essential hypertension. 856 41

The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension due to an inborn error of cortisol metabolism and is characterized by hypokalemia and low renin levels despite subnormal or normal levels of aldosterone and other known mineralocorticoids. The syndrome is attributable to congenital deficiency of the enzyme 11 beta-hydroxydehydrogenase (11 beta-HSD), which converts cortisol (F) to biologically inactive cortisone. This results in a prolonged half-life of F, which acts at the kidney level as a potent mineralocorticoid (MC). In fact, both F and aldosterone have similar affinities in vitro for type I MC receptor (MR), and 11 beta-HSD activity protects the MR in vivo from the higher circulating levels of F. The biochemical marker of this disorder is an increased ratio of tetrahydrocortisol (THF) + allo-THF/tetrahydrocortisone (THE) in the urine, which has been found in more than 20 patients described to date, together with evidence of a more general defect in steroid ring A reduction. Only a few cases (the so-called type II form) described in Italy differ from the classic form having a normal THF/THE ratio, but in both forms the ratio of free urinary F/E has recently been found to be similarly high. Dexamethasone is the treatment of choice but is often inadequate in long term control of high blood pressure. Acquired forms of AME are those consequent on abuse of licorice or carbenoxolone, which both inhibit 11 beta-HSD; the latter also inhibits the reverse 11-oxoreductase reaction leading to somewhat different abnormalities of urinary cortisol/cortisone. So far, two isoenzymes of 11 beta-HSD have been purified and cloned; 11 beta-HSD type 1 is NADP-dependent, abundant in liver, lung, and testis, and catalyzes both 11 beta-dehydrogenation and 11 beta-oxoreduction; no mutation in its gene was detected in patients with AME. A second NAD-dependent isoenzyme is present in kidney and placenta and catalyzes dehydrogenation only. Very recently (1995) two groups have independently demonstrated the presence of mutations in its gene, located in chromosome 16q22. New and co-workers found a point mutation in exon 6 of two affected siblings of an Iranian family, while White and co-workers in parallel studies showed point mutations or small deletions in both alleles in nine unrelated patients; importantly, expression studies showed minimal or absent activity for almost all the mutant sequences. No definite mutations have been so far identified in patients with AME type II. AME is thus the third single gene cause of human hypertension to be described, after glucocorticoid remediable aldosteronism in 1992 and Liddle's syndrome in 1994.
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PMID:Apparent mineralocorticoid excess: type I and type II. 873 99

The anti-ischemic effects of organic nitrates are rapidly attenuated due to the development of nitrate tolerance. The mechanisms underlying this phenomenon likely involve several independent factors. As a vasodilator, nitroglycerin activates compensatory neurohumoral mechanisms such as the renin-angiotensin system and increases catecholamine and vasopressin levels, all of which may attenuate its vasodilator potency. Tolerance may be also due to the inability of the vessel to dilate after prolonged treatment with the nitrate. More recent experimental studies have challenged traditional tolerance concepts by demonstrating that tolerance is not associated with sulfhydryl group depletion, reduced nitroglycerin biotransformation, or desensitization of the target enzyme guanylyl-cyclase. Experimental and clinical observations suggest that tolerance may be the consequence of intrinsic abnormalities of the vasculature, including enhanced endothelial production of oxygen-derived free radicals secondary to an activation of NAD(P)H-dependent oxidases and an activation of PKC. Superoxide degrades nitric oxide derived from nitroglycerin (NTG) while C activation causes enhanced sensitivity of the vasculature to circulating neurohormones such as catecholamines, angiotensin II, and serotonin, all of which may compromise the vasodilator potency of NTG. Interestingly, these vascular consequences of in vivo NTG treatment such as superoxide production and PKC activation can be mimicked in vitro by incubating cultured endothelial and smooth muscle cells with angiotensin II. Furthermore, nitrate tolerance and rebound following sudden cessation of prolonged NTG therapy can be prevented by concomitant treatment with high-dose angiotensin-converting enzyme inhibition, angiotensin type 1 receptor blockade, or antioxidants such as hydralazine. Thus one can conclude that neurohumoral counterregulatory mechanisms such as increased circulating levels of angiotensin II may be at least in part responsible for tolerance mechanisms at the cellular level.
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PMID:Evidence for a role of oxygen-derived free radicals and protein kinase C in nitrate tolerance. 942 22

The endothelium modulates vascular tone by producing vasodilator and vasconstrictor substances. Of these, the best characterized and potentially most important are nitric oxide (NO.) and O2-.. These small molecules exhibit opposing effects on vascular tone and chemically react with each other in a fashion that negates their individual effects and leads to the production of potentially toxic substances, such as peroxynitrite (ONOO-). These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. The precise O2-. source within vascular tissue remains to be determined. Recent work demonstrated that in endothelial cells as well as in vascular smooth muscle cells, a membrane-associated NAD(P)H-dependent oxidase represents the most significant O2-. source. Interestingly, this oxidase is activated upon stimulation with angiotension II, suggesting that under all conditions of an activated circulating and/or local renin-angiotensin system endothelial dysfunction secondary to increased vascular O2-. production is expected.
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PMID:Role for NADPH/NADH oxidase in the modulation of vascular tone. 1041 49

In different cardiovascular disease states, oxidative stress decreases the bioavailability of endothelial NO, resulting in endothelial dysfunction. An important molecular source of reactive oxygen species is the enzyme family of NAD(P)H oxidases (Nox). Here we provide evidence that the vascular Nox isoforms Nox1 and Nox4 appear to be involved in vascular oxidative stress in response to risk factors like angiotensin II (Ang II) in vitro as well as in vivo. Nox mRNA and protein levels were quantified by real-time RT-PCR and Western blotting, respectively. Nox1 and Nox4 were expressed in the vascular smooth muscle cell (VSMC) line A7r5 and aortas and kidneys of rats. Upon exposure of A7r5 cells to Ang II (1 microM, 4 h), Nox1 and Nox4 mRNA levels were increased 6-fold and 4-fold, respectively. Neither the vasoconstrictor endothelin 1 (up to 500 nM, 1-24 h) nor lipopolysaccharide (up to 100 ng/ml, 1-24 h) had any effect on Nox1 and Nox4 expression in these cells. Consistent with these observations made in vitro, aortas and kidneys of transgenic hypertensive rats overexpressing the Ren2 gene [TGR(mRen2)27] had significantly higher amounts of Nox1 and Nox4 mRNA and of Nox4 protein compared to tissues from normotensive wild-type animals. In conclusion, Nox4 and Nox1 are upregulated by the renin-angiotensin system. Increased superoxide production by upregulated vascular Nox isoforms may diminish the effectiveness of NO and thus contribute to the development of vascular diseases. Nox1 and Nox4 could be targeted therapeutically to reduce vascular reactive oxygen species production and thereby increase the bioavailability of NO.
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PMID:Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo. 1172 18

Oxidative stress and low-grade inflammation are hallmarks of diabetes mellitus. We explored protective, blood pressure-independent effects of the angiotensin II type 1 (AT(1)) receptor antagonist candesartan and the selective beta(1)-adrenoceptor antagonist metoprolol. Diabetes mellitus was induced in 8-week-old Sprague-Dawley rats after injection of streptozotocin. Diabetic rats were randomized to treatment with candesartan or metoprolol in sub-antihypertensive doses or to placebo treatment. In the quadriceps, musculature markers of oxidative stress and inflammation were determined. Function of the inherent vascular bed was measured in vivo in the autoperfused hindlimb. Increases in NAD(P)H activity, expression of its cytosolic subunit p22(phox) and of endothelial NO synthase e(NOS) displayed enhanced oxidative stress. Upregulated intercellular (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and of inducible NOS (iNOS) revealed inflammatory processes. Diabetes was associated with severe impairment of endothelium-dependent and -independent vasodilatation. Candesartan, but not metoprolol, reduced NAD(P)H activity, attenuated diabetes-induced over-expression of p22(phox) and eNOS mRNA as well as ICAM-1, VCAM-1, iNOS and eNOS immunoreactivity and led to a substantial improvement of endothelium-dependent vasodilatation (+46.3% vs. placebo treatment; P<0.05). Angiotensin AT(1) receptor antagonism, but not beta(1)-adrenoceptor antagonism, ameliorates diabetes-generated oxidative stress, indicating a pivotal role of the renin-angiotensin system in the development of diabetic complications.
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PMID:Protection against oxidative stress in diabetic rats: role of angiotensin AT(1) receptor and beta 1-adrenoceptor antagonism. 1613 67

Angiotensin II activates (via type 1 receptors) NAD(P)H-dependent oxidases, which are a major source of superoxide, and is relevant in the pathogenesis of several cardiovascular diseases and certain degenerative changes associated with ageing. Given that there is a brain renin-angiotensin system and that oxidative stress is a key contributor to Parkinson's disease, we investigated the effects of angiotensin II and angiotensin type 1 (AT(1)) receptor antagonists in the 6-hydroxydopamine model of Parkinson's disease. Rats subjected to intraventricular injection of 6-hydroxydopamine showed bilateral reduction in the number of dopaminergic neurons and terminals. Injection of angiotensin alone did not induce any significant effect. However, angiotensin increased the toxic effect of 6-hydroxydopamine. Rats treated with the AT(1) receptor antagonist ZD 7155 and then 6-hydroxydopamine (with or without exogenous administration of angiotensin) showed a significant reduction in 6-hydroxydopamine-induced oxidative stress (lipid peroxidation and protein oxidation) and dopaminergic degeneration. Dopaminergic degeneration was also reduced by the NAD(P)H inhibitor apocynin. Angiotensin may play a pivotal role, via AT(1) receptors, in increasing the oxidative damage of dopaminergic cells, and treatment with AT(1) antagonists may reduce the progression of Parkinson's disease.
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PMID:Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons. 1662 Nov 67

Changes in the hemodynamic environment (e.g., hypertension, increased blood flow/shear stress) are known to lead to vascular remodeling; however, the underlying mechanisms by which hemodynamic forces control gene expression in vascular cells are not yet completely understood. This review considers how mechanosensitive generation of reactive oxygen species (ROS) by NAD(P)H oxidases and other sources interacts with downstream signaling systems [including activation of nuclear factor kappa B (NF-kappaB) and AP-1] that modulate the phenotype of endothelial and smooth muscle cells, leading to vascular remodeling. We propose a model for an interaction between direct mechanosensitive ROS signaling and pathways activated by pressure-induced upregulation of prooxidant paracrine signaling mechanisms [local renin-angiotensin system, TNF-alpha- converting enzyme (TACE)/tumor necrosis factor alpha (TNF-alpha) system, and endothelin signaling].
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PMID:Mechanosensitive production of reactive oxygen species in endothelial and smooth muscle cells: role in microvascular remodeling? 1691 Jul 60

Oxidative stress produced through reactive oxygen species (ROS) enhancement is considered to play a key role in the development and maintenance of hypertension. In the vasculature, the most important source of ROS is the reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase enzyme. The principal stimulus of this enzyme is angiotensin II (Ang II). However, oxidative stress seems to be present in virtually all forms of hypertension including low-renin hypertension, where the levels of Ang II are reduced. For this reason, the question is if ROS generation is induced by Ang II or it is a consequence of hypertension. We used as hypertensive model the aortic coarctated rats, which were treated with losartan or minoxidil for 7 days. Thoracic aortic segments were excised, and the NAD(P)H oxidase subunits expression, oxidative stress parameters, and heme oxygenase-1 abundance were evaluated. Hypertensive animals had an increase in the activity and expression of NAD(P)H oxidase and, as a consequence, in the oxidative stress parameters. Interestingly, either losartan or minoxidil administration blunted those parameters, indicating that arterial pressure is the key factor in the development of oxidative stress in the hypertensive aorta. We suggest that antihypertensive drug administration at the beginning of this pathology delays the oxidative stress generation, thus preventing the aggravation of this disease.
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PMID:Lowering arterial pressure delays the oxidative stress generation in a renal experimental model of hypertension. 1968 45


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