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 isolated perfused rat kidney was used to examine the effect of insulin on renin release (RR). Insulin produced a dose-dependent reduction of RR when added to the perfusate at concentrations between 10 and 1,000 microU/ml. When kidneys were perfused with a calcium-free perfusate, RR increased nearly fivefold. Insulin (1,000 microU/ml) not only failed to suppress RR in calcium-free perfusions but stimulated it. The addition of verapamil (10(-5) M) to the perfusate likewise prevented the insulin inhibition of RR. Perfusion without potassium reduced RR to one-third of control values. The addition of insulin to kidneys perfused without potassium further suppresses RR. We conclude that at concentrations similar to those found in plasma, insulin modulates renin secretion. This process requires the influx of calcium possibly through insulin receptor-operated channels.
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PMID:Suppression of renin secretion by insulin: dependence on extracellular calcium. 636 26

1. In severe, familial hypertension, we have reported that the proportion of patients homozygous for the deletion allele of an insertion/deletion polymorphism of the angiotensin I-converting enzyme gene is markedly decreased in older age groups, suggesting that this genotype is associated with increased risk of premature death. The aim of the present study was to examine the relationship with age, of variants of other genes that encode proteins having an influence on the cardiovascular system. 2. Genotypes of 13 different variants at 12 relevant genetic loci were determined by either Southern blotting, followed by hybridization probing, or polymerase chain reaction techniques, as appropriate, using genomic DNA extracted from blood leukocytes. Genotype numbers were then assigned to the age categories of < 50, 50-59 and > or = 60 years. 3. Polymorphisms at the atrial natriuretic factor, antithrombin III, renin, angiotensinogen, neuropeptide-Y Y1 receptor, insulin, alpha 2-adrenoceptor, beta 1-adrenoceptor, growth hormone, low density lipoprotein receptor, insulin receptor and renal kallikrein gene loci were found to display similar allele frequencies in each age group of hypertensives, as well as in normotensive controls. 4. In conclusion, we were unable to detect any difference with age for a range of variants of genes whose products have cardiovascular significance, suggesting that, like most polymorphisms, they carry no selective survival advantage or disadvantage in the hypertensive and normotensive population groups studied.
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PMID:Frequencies of variants of candidate genes in different age groups of hypertensives. 788 87

Insulin has been postulated to play a role in the pathophysiology of essential hypertension via an antinatriuretic action. To further explain the sodium insulin interaction in the kidney, we studied effects of different salt intakes on insulin receptor binding and mRNA levels in tissues from rats maintained on 0.07%, 0.3%, or 7.5% NaCl for 14 days. Scatchard analysis of competition data from in situ autoradiography studies resulted in curvilinear profiles, indicating the presence of either two classes of receptors or a single class of receptors with a negative cooperative hormone-receptor interaction. When data were analyzed using the two-site model, binding capacity of the high-affinity receptor site was significantly less in high-salt-fed rats. No significant differences between dietary groups were observed in apparent dissociation constants of the two receptor sites or in maximal binding capacity of the low-affinity, high-capacity site. Analysis of insulin binding to glomeruli, cortex, outer medulla, and inner medulla indicated that the high-salt diet was associated with decreased receptor density in all regions studied. Insulin receptor mRNA, as quantified by Northern and slot blot analysis, was inversely related to salt intake in absence of a change in plasma glucose, insulin, and corticosterone levels. Both 7.2- and 9.4-kb transcripts were similarly affected by dietary sodium content. Plasma renin concentration and renal renin mRNA levels were decreased but blood pressure was not affected by high-salt diet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of dietary sodium chloride on insulin receptor number and mRNA levels in rat kidney. 830 82

Both the density and level of mRNA encoding insulin receptors in the kidney are inversely related to the dietary sodium content, suggesting a feedback mechanism that limits the insulin-induced sodium retention when extracellular fluid volume is expanded. Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. Non-diabetic and diabetic rats were infused for 7 days with either vehicle or angiotensin II at a rate of 200 ng. kg-1. min-1. In a separate experiment, normal rats were treated with an angiotensin converting enzyme inhibitor (captopril, 100 mg/dl in the drinking water) or vehicle for 7 days. Regional analysis of insulin receptor binding in the kidney and renal arteries was performed by an in situ technique using computerized microdensitometry and emulsion autoradiography. Insulin receptor mRNA levels were determined in renal and hepatic tissue by Northern blot hybridization and normalized with 28S rRNA. No differences in blood pressure were observed among diabetic and non-diabetic rats infused with either vehicle or angiotensin II, whereas captopril-treated rats had significantly lower blood pressure levels than their respective controls. Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. Insulin receptor number was significantly greater in the renal cortex of diabetic rats than in non-diabetics, whereas no significant differences were found in the outer medulla, inner medulla, or renal arteries. Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. Thus, diabetic rats have increased insulin receptor binding and mRNA levels in comparison to non-diabetic rats. Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin.
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PMID:Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. 966 61

The first molecular genetic association with human essential hypertension (HT) involved the insulin receptor gene (INSR). This highly significant result in Caucasians was for an insertion/deletion polymorphism in intron 9. A polymorphism in exon 8 showed a weak association, but a microsatellite in intron 2 proved negative for HT, although has shown an association with plasma insulin in Japanese. A similar spectrum of genetic associations for variants spanning INSR has been noted for insulin-dependent diabetic patients with rapidly-progressing renal disease, a subgroup having a strong family history of essential HT. Association with HT has also been found for an INSR variant in CHinese. Insulin resistance secondary to an INSR 'defect', or other causes, would increase insulin, which has cardiovascular effects, and insulin can raise angiotensinogen. Also, insulin is co-secreted with amylin, which can increase renin secretion. In the spontaneously HT rat there is evidence for reduced down-regulation of INSR expression in response to NaCl-loading, consistent with a promoter effect. When combined with observations of insulin resistance in essential HT patients and their pre-HT offspring, the possibility of dys-regulation of INSR merits attention in disease etiology in a proportion of essential HT patients.
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PMID:Insulin receptor gene in hypertension. 924 38

To investigate potential interactions between angiotensin II (AII) and the insulin signaling system in the vasculature, insulin and AII regulation of insulin receptor substrate-1 (IRS-1) phosphorylation and phosphatidylinositol (PI) 3-kinase activation were examined in rat aortic smooth muscle cells. Pretreatment of cells with AII inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1 by 60%. While AII did not impair insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) beta-subunit, it decreased insulin-stimulated tyrosine phosphorylation of IRS-1 by 50%. AII inhibited the insulin-stimulated association between IRS-1 and the p85 subunit of PI 3-kinase by 30-50% in a dose-dependent manner. This inhibitory effect of AII on IRS-1/PI 3-kinase association was blocked by the AII receptor antagonist saralasin, but not by AT1 antagonist losartan or AT2 antagonist PD123319. AII increased the serine phosphorylation of both the IR beta-subunit and IRS-1. In vitro binding experiments showed that autophosphorylation increased IR binding to IRS-1 from control cells by 2.5-fold versus 1.2-fold for IRS-1 from AII-stimulated cells, suggesting that AII stimulation reduces IRS-1's ability to associate with activated IR. In addition, AII increased p85 serine phosphorylation, inhibited the total pool of p85 associated PI 3-kinase activity, and decreased levels of the p50/p55 regulatory subunit of PI 3-kinase. These results suggest that activation of the renin-angiotensin system may lead to insulin resistance in the vasculature.
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PMID:Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels. A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. 941 Aug 92

The main task in hypertension research is to explain genetic causes of a raised blood pressure. It is anticipated that advances in this area will promote not only a better understanding of the pathophysiology of hypertension but will make a more aimed approach to early diagnosis, prevention and therapy of essential hypertension possible. The greatest problems in investigations of the heredity of hypertension are; a) in cardiovascular control mechanisms several genes participate; b) factors of the external environment which act on a long-term basis interfere with the relationship of the genotype and phenotype individually, within the family and regionally; c) the blood pressure is a continuous variable and the definition of the phenotype of hypertension is inaccurate; d) inadequate number of family members where hypertension segregates. New methods in molecular biology and statistical genetics made it possible to assess a number of highly polymorphous genetic signs in several candidate genes and the subsequent investigation of their possible role in the pathogenesis of hypertension. The majority of hitherto accomplished studies was concentrated on genes coding different components of the renin-angiotensin system: renin, ACE, angiotensinogen and angiotensin II receptors. So far the most promising, though not consistent, results were obtained for angiotensinogen and the insulin receptor. Work focused on the relationship of the polymorphism of genes for ANF, growth hormone and kallikrein to essential hypertension is negative. The genetic heterogeneity of the human population, physiological differences in the genesis of high blood pressure in different ethnical groups and inaccurate measurements of specific phenotypes can contribute to different results of different studies.
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PMID:[Molecular genetics methods in the study of hereditary essential hypertension]. 951 Dec 64

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

Insulin resistance and hypertension commonly occur together. Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. This raises the possibility that the renin-angiotensin system may interact with insulin signalling. We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. This leads to binding of IRS-1 and IRS-2 to PI3-kinase. However, in contrast to the effect of insulin. IRS-1- and IRS-2-associated PI3-kinase activity is inhibited by AII in a dose-dependent manner. Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. The in vivo effects of AII are mediated via the AT1 receptor. The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. These actions result in the inhibition of normal interactions between the insulin signalling pathway components. Thus, we believe that AII negatively modulates insulin signalling by stimulating multiple serine phosphorylation events in the early components of the insulin signalling cascade. Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension.
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PMID:Crosstalk between insulin and angiotensin II signalling systems. 1032 50

Insulin resistance and hyperinsulinemia have been observed in essential hypertension. The selective impairment of glucose metabolism in skeletal muscle may accompanied hyperinsulinemia and raise blood pressure through sympathetic nervous system and/or renin-angiotensin system activation, renal sodium retention, proliferation of vascular smooth muscle and leptin. Recently, molecular techniques have applied for investigating the mechanisms of insulin resistance. The mutation of insulin receptor gene, changes of muscle fiber composition and muscle blood flow, abnormalities of insulin signal transduction, and TNF-alpha are considered as involvement of insulin resistance in the skeletal muscle. While further study will be necessary to clarify the mechanisms of insulin resistance and hypertension.
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PMID:[Insulin resistance syndrome]. 1139 82


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