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)

Although angiotensin II has long been considered to represent the end product of the renin-angiotensin system (RAS), there is accumulating evidence that it encompasses additional effector peptides with diverse functions. In this respect, angiotensin IV (Ang IV) formed by deletion of the two N terminal amino acids, has sparked great interest because of its wide range of physiological effects. Among those, its facilitatory role in memory acquisition and retrieval is of special therapeutic relevance. High affinity binding sites for this peptide have been denoted as AT(4)- receptors and, very recently, they have been proposed to correspond to the membrane-associated OTase/ IRAP aminopeptidase. This offers new opportunities for examining physiological roles of Ang IV in the fields of cognition, cardiovascular and renal metabolism and pathophysiological conditions like diabetes and hypertension. Still new recognition sites may be unveiled for this and other angiotensin fragments. Recognition sites for Ang-(1-7) (deletion of the C terminal amino acid) are still elusive and some of the actions of angiotensin III (deletion of the N terminal amino acid) in the CNS are hard to explain on the basis of their interaction with AT(1)-receptors only. A more thorough cross-talk between in vitro investigations on native and transfected cell lines and in vivo investigations on healthy, diseased and transgenic animals may prove to be essential to further unravel the molecular basis of the physiological actions of these small endogenous angiotensin fragments.
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PMID:Cellular targets for angiotensin II fragments: pharmacological and molecular evidence. 1258 63

A local paracrine angiotensin (ANG) system influences the insulin sensitivity and cell differentiation of adipose tissue. The limited view of a merely systemic renin-angiotensin-aldosterone-system with ANG II (1-8) as the main mediator of ANG-related effects may oversimplify the situation. The aim was to analyze the degradation of ANG by using capillary electrophoresis (CE) techniques. The supernatant of cultured 3T3-L1 adipocytes was used directly, and some data on degraded peptides were combined with a biological effect. The formation of several peptides such as ANG II (1-8), -III (2-8), -IV (3-8), and ANG (1-7) as degradation products is demonstrated; in addition low levels of ANG (3-7) are identified. The concentrations of the peptides ANG III (2-8) and ANG IV (3-8) (both are AT(4) receptor agonists) are modified in the vicinity of adipose tissue cells by amino-terminal degradation which resulted in ANG (3-8), -(4-8) and -(5-8). ANG IV (3-8) and ANG II (1-8) were biologically highly effective in inhibiting IRAP (insulin regulated aminopeptidase, part of the AT(4) receptor). It is observed that ANG (1-7) is the main degradation product derived from ANG I via ANG (1-9) and that ANG III (2-8) is one important regulated peptide for IRAP.
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PMID:Local formation of angiotensin peptides with paracrine activity by adipocytes. 1979 42

Although clinical studies suggested that blockade of the renin-angiotensin system may prevent diabetes, the mechanism is uncertain. As a follow-up to an earlier study, we investigated how des-aspartate-angiotensin-1 (DAA-1) and its metabolite, angiotensin IV (Ang-IV) improved glucose tolerance in diet-induced hyperglycaemic mice. Male C57BL/6J mice were fed a high-fat-high-sucrose (HFD) or normal (ND) diet for 52 weeks. HFD animals were orally administered either DAA-I (600nmol/kg/day), Ang-IV (400nmol/kg/day) or distilled water. Body weight, blood glucose and insulin were measured fortnightly. Inflammatory and insulin signalling transducers that are implicated in hyperglycaemia were analyzed in skeletal muscles at 52 weeks. HFD animals developed hyperglycemia, hyperinsulinemia and obesity. DAA-I and Ang-IV improved glucose tolerance but had no effect on hyperinsulinemia and obesity. Skeletal muscles of HFD animals showed increased level of ROS, gp91 of NADPH oxidase, pJNK and AT(1)R-JAK-2-IRS-1 complex. Both DAA-I and Ang-IV attenuated these increases. Insulin-induced activation of IR, IRS-1, IRS-1-PI3K coupling, phosphorylation of Akt, and GLUT4 translocation were attenuated in skeletal muscles of HFD animals. The attenuation was significantly ameliorated in DAA-I-treated HFD animals. In corresponding Ang-IV treated animals, insulin induced IRAP and PI3K interaction, activation of pAkt and GLUT4 translocation, but no corresponding activation of IR, IRS-1 and IRS-1-PI3K coupling were observed. DAA-I and Ang-IV improved glucose tolerance, insulin signalling, and para-inflammatory processes linked to hyperglycaemia. DAA-I acts via the angiotensin AT(1) receptor and activates the insulin pathway. Ang-IV acts via IRAP, which couples PI3K and activates the later part of the insulin pathway.
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PMID:Des-aspartate-angiotensin-I and angiotensin IV improve glucose tolerance and insulin signalling in diet-induced hyperglycaemic mice. 2180 28

Essential hypertension is one of the major contributors to premature morbidity and mortality due to the incresased risk for coronary heart disease, stroke, renal disease, peripheral vascular disease and vascular dementia for both men and women. However, its basic causes remain unknown. In the present work we studied the activity of several proteolytic regulatory enzymes related to renin-angiotensin-system (RAS) (aminopeptidase A, APA; aminopeptidase N, APN; aminopeptidase B, APB; and insulin-regulated aminopeptidase, IRAP); with oxytocin regulation (oxytocinase); with the metabolism of GnRH and TRH (pyrrolidone carboxypeptidase, Pcp); and with enkephalins metabolism (enkephalindegrading activity, EDA), to elucidate their role in the mechanisms responsible of essential hypertension and to discuss the possible gender differences. Serum samples of 53 individuals with essential hypertension and 60 healthy volunteers were collected and used to assay enzyme activities, gonad hormones testosterone and estradiol, TSH and free thyroxin (fT4). Differences were observed in APA, APN, Pcp and EDA specific activities, and in serum gonad hormone levels between hypertensive and control groups. Only Pcp activity showed gender differences. Regarding the RAS, APA is reduced while APN is increased, suggesting increased levels of angiotensin II and a facilitation of the conversion of angiotensin III in angiotensin IV. Thus, the changes in several RAS-regulating specific activities and other enzyme activities involved in the neuroendocrine modulation of gonad and stress-related functions are related to essential hypertension with minor gender differences. Therefore, aminopeptidases constitute new elements for the knowledge of the causes of essential hypertension and an alternative as therapeutic targets against the illness.
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PMID:Circulating aminopeptidase activities in men and women with essential hypertension. 2393 Dec 76

The renin-angiotensin system (RAS) is undisputedly one of the most prominent endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) vasoactive systems in the physiological regulation of neural, cardiovascular, blood pressure, and kidney function. The importance of the RAS in the development and pathogenesis of cardiovascular, hypertensive and kidney diseases has now been firmly established in clinical trials and practice using renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, type 1 (AT1) angiotensin II (ANG II) receptor blockers (ARBs), or aldosterone receptor antagonists as major therapeutic drugs. The major mechanisms of actions for these RAS inhibitors or receptor blockers are mediated primarily by blocking the detrimental effects of the classic angiotensinogen/renin/ACE/ANG II/AT1/aldosterone axis. However, the RAS has expanded from this classic axis to include several other complex biochemical and physiological axes, which are derived from the metabolism of this classic axis. Currently, at least five axes of the RAS have been described, with each having its key substrate, enzyme, effector peptide, receptor, and/or downstream signaling pathways. These include the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor, the ANG II/APA/ANG III/AT2/NO/cGMP, the ANG I/ANG II/ACE2/ANG (1-7)/Mas receptor, the prorenin/renin/prorenin receptor (PRR or Atp6ap2)/MAP kinases ERK1/2/V-ATPase, and the ANG III/APN/ANG IV/IRAP/AT4 receptor axes. Since the roles and therapeutic implications of the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor axis have been extensively reviewed, this article will focus primarily on reviewing the roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases.
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PMID:The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. 2861 67