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)

Obese spontaneously hypertensive rats (SHR) develop nephropathy with severe proteinuria, but lean littermates do not develop renal disease. Intrarenal angiotensin has been suggested to contribute to nephropathy in other experimental models. We examined the regulation of angiotensin receptors as a reflection of target tissue response to possible changes in the renin-angiotensin system. We visualized angiotensin receptors in kidneys of 6-8-month-old obese SHR and their lean littermates. Both obese and lean rats were hypertensive as determined by tail-cuff or by direct measurement. Histologic studies showed early glomerular sclerosis in obese but not lean rats. Autoradiographic visualization of angiotensin receptor binding sites in both obese and lean SHR showed glomeruli and medullary rays having the highest levels of binding with additional diffuse labeling in cortex and outer medulla. In obese rats, binding was reduced relative to lean littermates, particularly in the medulla, while intense binding in glomeruli was preserved. Loss of receptors did not reflect tissue damage, since the medulla showed no pathological changes. Biochemical assays of the binding of subtype-selective antagonists to 125I-angiotensin sites in intact sections showed that both losartan-sensitive and PD 123319-sensitive sites were decreased in nephrotic obese rats. We conclude that specific binding sites for angiotensin are decreased in obese SHR with early glomerular sclerosis, suggesting that angiotensin receptors may be regulated by pathogenic processes in this model of renal disease.
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PMID:Renal angiotensin receptor mapping in obese spontaneously hypertensive rats. 850 89

Despite the wide range of anti-hypertensive drugs currently available many more are being developed, including entirely novel classes of compounds. This is not entirely surprising as a minority of patients do not respond to existing agents or are unable to tolerate them at therapeutic doses. It is also true that hypertension represents a very large international market. This brief review deals with the following classes of agents which are at various stages of development: (1) angiotensin receptor antagonists of the AT1 subtype, the first of which has recently been marketed in the UK; (2) renin inhibitors, whose development has been hindered by the poor bioavailability of all but the most recent compounds; (3) imidazoline (I1) receptor agonists, centrally acting drugs with relatively little sedating activity; (4) potassium channel openers, which act as potent vasodilators; (5) neutral endopeptidase inhibitors which potentiate the actions of atrial natriuretic peptides; and (6) endothelin antagonists, which are still in pre-clinical development. The potential clinical significance of these compounds is discussed.
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PMID:New ideas for treating hypertension. 852 85

So far, two angiotensin receptor subtypes, called AT1 and AT2, have been described in an animal model and in human. AT1 mediates almost all known effects of angiotensin II and its gene sequence and regulation is well studied. In contrast, only few data on function and regulation of AT2 are available. The complete mRNA sequence of AT2 has only recently been cloned and sequenced. The angiotensin receptors' receptor density and subtype distribution is organ specific. In the rat, lowest densities are found in the myocardium, followed by kidney, liver, adrenal medulla and cortex. The percentage of AT1 in the different organs amounts to 80, 85, 90, 57 and 10%. Angiotensin receptor subtypes have also been quantitated in human myocardium. There, the relatively unknown subtype AT2 dominates (67%). Myocardial receptor density is low, amounting to about 11 fmol/mg protein corresponding to 1/20-1/50 of the density of beta-adrenergic receptors. Angiotensin receptors in the human heart are present on cardiac fibroblasts and induce proliferation of these cells. Blockade of the renin angiotensin system by ACEI and AT1 antagonists in the rat downregulates angiotensin receptors in liver, kidney and adrenals to about 50% in an organ- and subtype specific manner, whereas cyclosporin A upregulates receptors twice. In end-stage human heart failure, but not in early stages, angiotensin receptors are downregulated to 1/3 of control values. Regulator mechanisms at transcriptional level have been elucidated by reporter gene assays; PMA, an activator of proteinkinase C, stimulates the transcription of the AT1 gene. The organ- and subtypespecific regulation of angiotensin receptors by pharmacological agents and/or cardiovascular diseases can contribute to the understanding of these drugs and of the pathophysiology of the corresponding diseases.
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PMID:[Angiotensin receptors--organ and subtype specific regulation in cardiovascular diseases by modulation of the renin-angiotensin system. Studies of the rat model and in human myocardium]. 858 75

Left ventricular remodeling is a dynamic process that occurs in reaction to an insult to the myocardium. The response to either loss of cells, as may occur following myocardial infarction, or to hemodynamic overload, as may occur in aortic stenosis, is an attempt to maintain cardiac output and normalize wall tension. This is accomplished through the activation of the renin-angiotensin system and hypertrophy of noninfarcted segments of the myocardium. in the case of moderate or large infarctions these mechanisms fail to normalize wall stress. The stimulus to further remodeling remains, viable myocytes hypertrophy (with greater increases in cell length than width), the mass-to-volume ratio increases, and an exponential increase in wall stress results. This increase in myocyte tension has been associated with premature myocyte cell death. Thus, a vicious cycle is established wherein overstretch of the myocardium while sustaining cardiac output leads to progressive myocyte loss and left ventricular dilation. The renin-angiotensin system plays an integral role in this process. Its inhibition by angiotensin-converting enzyme (ACE) inhibitors both chronically and immediately after myocardial infarction has been shown to decrease left ventricular volumes and reduce mortality. Controversy exists regarding the mechanism through which ACE inhibitors exert their effects. ACE inhibitors reduce afterload/preload, circulating angiotensin II levels, and raise circulating levels of bradykinin. It is not yet clear which mechanism is responsible for the greatest impact on left ventricular dilation and mortality. inhibition of the renin-angiotensin system is clearly beneficial to cardiac performance as well as morbidity and mortality when myocardium is lost and heart failure ensues. Specific modes of action require further definition, including local and systemic effects. Possible benefits of angiotensin receptor blockade versus augmentation of bradykinin requires definition, setting the stage for further study, while the beneficial therapeutic use of these agents continues.
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PMID:The renin-angiotensin system in left ventricular remodeling. 863 27

Characterization and regulation of angiotensin II (AII) receptor binding sites was performed in rat membrane preparations from nonadipose (liver, lung) and adipose (interscapular (ISBAT) and periaortic (PA) brown adipose tissue; epididymal (EF) and retroperitoneal (RPF) white adipose tissue). In membrane preparations from brown and white adipose sources, [125I]AII saturation binding revealed a single, high affinity (Kd range of 0.3 -0.6 nM) binding site with a modest AII receptor density (Bmax range of 17-120 fmol/mg protein) comparable to rat lung (130 fmol/mg protein). White adipose tissue contained a greater number of AII receptor sites than brown adipose tissue. Competition displacement studies demonstrated the AT1 receptor is the only angiotensin receptor subtype localized in adipose tissue, with the rank order for competition of [125I]AII binding in all adipose tissues examined AIII > AII > losartan > angiotensin I (AI) > PD123319. The AT2 specific receptor antagonist, PD123319, was ineffective at displacing [125I]AII binding in all adipose tissues examined. Since components of the renin-angiotensin system are regulated in adipose tissue, we determined if the AII receptor is also regulated in the obese state. AII receptor binding characteristics were determined in liver, lung, ISBAT and EF membrane preparations from adult Zucker obese (fa/fa) and lean (Fa/?) rats. AII receptor density was decreased in liver from obese rats. In contrast, the affinity for [125I]AII binding was not altered in tissues from obese rats. In a separate group of obese and lean rats, regulation of the AII receptor by phenobarbital (PB) was examined. Administration of PB restored AII receptor density in liver from obese rats to levels obtained in lean rats. In summary, these results demonstrate the presence of AT1 receptor sites in brown and white adipose tissue. Moreover, AII receptor density is decreased in tissues from obese rats, with restoration of receptor density by administration of PB. Future studies will determine if PB regulates the AT1 receptor at the level of gene expression.
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PMID:Characterization and regulation of angiotensin II receptors in rat adipose tissue. Angiotensin receptors in adipose tissue. 872 84

The existence of a local cardiovascular renin-angiotensin system (RAS) is often invoked to explain the long-term beneficial effects of RAS inhibitors in heart failure and hypertension. The implicit assumption is that all components of the RAS are synthesized in situ, so that local angiotensin II formation may occur independently of the circulating RAS. Evidence for this assumption however is lacking. The angiotensin release from isolated perfused rat hearts or hindlimbs depends on the presence of renal renin. When calculating the in vivo angiotensin production at tissue sites in humans and pigs, taking into account the extensive regional angiotensin clearance by infusing radiolabeled angiotensin I or II, it was found that angiotensin production correlated closely with plasma renin activity. Moreover, in pigs the cardiac tissue levels of renin and angiotensin were directly correlated with their respective plasma levels, and both in tissue and plasma the levels were undetectably low after nephrectomy. Similarly, rat vascular renin and angiotensin decrease to low or undetectable levels within 48 h after nephrectomy. Aortic renin has a longer half life than plasma renin, suggesting that renin may be bound by the vessel wall. In support of this assumption, both renin receptors and renin-binding proteins have been described. Like ACE, renin was enriched in a purified membrane fraction prepared from cardiac tissue. Binding of renin to cardiac vascular membranes may therefore be part of a mechanism by which renin is taken up from plasma. It appears that the concept of a local RAS needs to be reassessed. Local angiotensin formation in heart and vessel wall does occur, but depends, at least under normal circumstances, on the uptake of renal renin from the circulation. Tissues may regulate their local angiotensin concentrations by varying the number of renin receptors and/or renin-binding proteins, the ACE level, the amount of metabolizing enzymes and the angiotensin receptor density.
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PMID:Local renin-angiotensin systems. 873 48

The actions of angiotensin II in the cardiovascular system are transmitted by two known and possibly some unknown angiotensin receptor types. AT1 and AT2 both correspond to G-protein-coupled receptors with seven hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and promoter sequences contributed to the understanding of receptor protein function and regulation. Angiotensin receptors with atypical binding properties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human ulcrus. In several animal models, receptors with high affinity for angiotensin (1-7) have been described. AT1 stimulation is mediated by the generation of phospholipid-derived second messengers, activation of protein kinase C, the MAPkinase pathway and of immediate early genes. Recently, phosphorylation and dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphorylation, internalization, modification of transcription rate and mRNA stability. Regulation is highly cell and organ specific and includes upregulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the cardiovascular system is relatively well established, there is little information regarding the role of AT2. Recent hypotheses suggest an antagonism between AT1 and AT2 at the signal transduction and the functional level. Transgenic animal models, particularly with targeted disruption of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been described in the AT1 and AT2 gene or neighbored regions and are used to analyze the association between gene defects and cardiovascular diseases. AT1 antagonists are now being introduced into the treatment of hypertension and potentially heart failure, and more interesting pharmacological developments are expected from the ongoing basic studies.
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PMID:Molecular biology of angiotensin receptors and their role in human cardiovascular disease. 877 61

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.
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PMID:Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. 882 46

Previous studies have shown that sodium depletion is associated with an increase in renal kallikrein-kinin system activity. This system may play an important role in counterbalancing the renal effects of the renin-angiotensin system. In this study, we examined whether the renal renin-angiotensin system participates in the regulation of renal bradykinin (BK) levels during sodium depletion. We measured changes in renal excretory and hemodynamic function, renal interstitial fluid (RIF) BK, and RIF and urinary guanosine 3',5'-cyclic monophosphate (cGMP) and prostaglandin E2 (PGE2) in conscious uninephrectomized dogs (n = 5) in sodium metabolic balance (10 meq/day) in response to intrarenal arterial administration of the renin inhibitor ACRIP (0.2 microgram.kg-1.min-1) or angiotensin II AT1-receptor blocker losartan (100 ng.kg-1.min-1). ACRIP and losartan increased urine flow rate from 0.75 +/- 0.06 to 1.6 +/- 0.03 and 1.5 +/- 0.05 ml/min, respectively (each P < 0.001), and urine sodium excretion from 5.4 +/- 0.7 to 18.3 +/- 1.3 and 15.9 +/- 1.2 meq/min, respectively (each P < 0.001). Glomerular filtration rate and renal plasma flow increased only during losartan administration (P < 0.05). ACRIP decreased RIF BK by 48%, from 33.1 +/- 3.8 to 17.4 +/- 4.1 pg/min (P < 0.01). ACRIP decreased RIF cGMP by 38%, from 0.69 +/- 0.08 to 0.43 +/- 0.1 pmol/min (P < 0.01); urinary cGMP by 16%, from 0.63 +/- 0.05 to 0.53 +/- 0.02 pmol/min (P < 0.05); and RIF PGE2 by 46%, from 10.5 +/- 1.1 to 5.7 +/- 1.1 pg/min (P < 0.01). Urinary PGE2 was unchanged by ACRIP. Losartan decreased RIF PGE2 by 71%, from 10.8 +/- 0.6 to 3.1 +/- 0.6 pg/min (P < 0.01) but failed to change RIF BK, RIF cGMP, urinary cGMP, or urinary PGE2. These data suggest that the renin-angiotensin system tonically stimulates renal BK production and cGMP formation via a non-AT1 angiotensin receptor and renal PGE2 production via the AT1 receptor.
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PMID:Renin-angiotensin system modulates renal bradykinin production. 889 5

The randomized angiotensin receptor antagonist--angiotensin converting enzyme (ACE)--Inhibitor Study (RAAS) was designed to test the hypothesis that the addition of an angiotensin II type 1 receptor blocking agent, losartan 50 mg/day, to an ACE-inhibitor, enalapril 10 mg twice a day (group 1), will be more effective than standard-dose enalapril 10 mg twice a day (group 2) or high-dose enalapril alone 20 mg twice a day (group 3), in blocking the activation of the renin angiotensin aldosterone system in patients with heart failure and left ventricular systolic dysfunction. The addition of an angiotensin II type 1 receptor blocking agent to an ACE inhibitor would theoretically block ACE as well as non-ACE-dependent angiotensin II formation while maintaining the potential beneficial effect of ACE inhibitor-induced bradykinin formation. One hundred twenty patients with left ventricular systolic dysfunction and moderate to severe heart failure despite treatment with an ACE inhibitor will be randomized to 1 of the 3 groups and followed for 6 weeks, with an optional long-term week extension to determine the safety and tolerability of the combination of losaratan and enalapril, its effectiveness in preventing rest and exercise-induced neurohumoral activation (plasma norepinephrine, N-terminal proatrial natriuretic factor, angiotensin II, and aldosterone), as well as quality of life and exercise performance (6-minute walk test).
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PMID:Rationale, background, and design of the randomized angiotensin receptor antagonist--angiotensin-converting enzyme inhibitor study (RAAS). 891 76


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