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 brain renin-angiotensin system has been implicated in the central regulation of the cardiovascular system, body water balance, and cyclic regulation of reproductive hormones and behaviors. It also exerts some influence over the secretion of pituitary hormones. This system appears to be complete with the necessary precursors and enzymes for the formation and degradation of biologically active forms of angiotensins and several binding subtypes that are presumed to mediate these and other functions. Much information is now available on the AT1 site which preferentially binds angiotensin II (AngII), but also binds angiotensin III (AngIII), and appears to be responsible for mediating the above described classic angiotensin physiologies and behaviors. Less is known about the functional importance of the AT2 site which also binds AngII but preferentially binds AngIII. This site has been implicated in vascular growth and cerebral blood flow. Recently, an AT4 site has been discovered and characterized that preferentially binds AngII (3-8), a fragment of AngII referred to as angiotensin IV (AngIV). This AT4 site is prominent in cerebral cortex, hippocampus, basal ganglia, cerebellum, and spinal cord, as well as several peripheral tissues including kidney, bladder, heart, spleen, prostate, adrenals, and colon. The AT4 site may mediate memory acquisition and recall and the regulation of blood flow. The function(s) of the AT4 receptor subtype in peripheral tissues is currently unknown, although it does appear to be involved in kidney blood flow.
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PMID:The angiotensin IV system: functional implications. 776 21

The kidney is not only the source of circulating renin, which determines the plasma concentration of angiotensin II, but it is also one of the main targets of angiotensin II. Thus, angiotensin II exerts an important physiologic influence on renal function through its ability to modulate renal hemodynamics as well as glomerular and tubular functions. Moreover, angiotensin II appears to contribute to the progressive deterioration of renal function commonly observed in renal diseases. The availability of new orally active, nonpeptide angiotensin II receptor antagonists lacking agonistic or kinin- and prostaglandin-inducing properties has offered the possibility of investigating further the renal influence of angiotensin II. Thus, it is now clear that most if not all renal effects of angiotensin II are mediated by the activation of AT1 receptors, although the AT2 subtype is present in the kidney. Furthermore, increasing experimental evidence indicates that the long-term renal protective effect of angiotensin-converting enzyme inhibitors is indeed due to the inhibition of the renin-angiotensin system rather than to the activation of non-angiotensin II mechanisms.
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PMID:Angiotensin II receptor antagonists and the kidney. 780 52

Protease nexin-1 (PN-1) is a potent inhibitor of serine proteases, such as thrombin and plasminogen activators, which is secreted into the extracellular space. Since PN-1 is induced following lesion of the sciatic nerve, the effect of substances known to accumulate at the site of injury was examined in primary cultures of Schwann cells. Among the cytokines, growth factors, mitogens, neurotrophins, and neuroactive peptides analyzed, only angiotensin II (Ang II), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) were found to regulate the expression of PN-1 on Schwann cells. While Ang II and CGRP caused downregulation, VIP acted as a positive modulator of PN-1. Displacement of Ang II binding using the selective ligands losartan and CGP 42112 led to a severalfold increase of PN-1 protein and mRNA over basal levels, indicating that the observed effect was mediated by specific binding sites. Indeed, the presence of AT1 and AT2 angiotensin receptor subtypes was demonstrated in cultured Schwann cells as well as in the rat sciatic nerve. Moreover, the detection of angiotensinogen- and renin-mRNA in these cultures suggested an endogenous production of Ang II. This data identified one of the mechanisms regulating PN-1 synthesis. Altogether our results indicate that neuropeptides can differentially control the proteolytic activity of the microenvironment, providing new aspects of neuron-glia interactions in the intact tissue and following nerve injury.
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PMID:Regulation of protease nexin-1 expression in cultured Schwann cells is mediated by angiotensin II receptors. 782 77

Previous studies showed that angiotensin II (AII) infusion increased survival in gerbils subjected to abrupt unilateral carotid ligation. Recently, stimulation of the AII AT2 receptor, reportedly effectively extended the blood pressure (BP) range of cerebral blood flow (CBF) autoregulation. We evaluated the survival of gerbils treated with PD-123319, a ligand of AT2 receptors, to test the hypothesis that restoration of BF to ischemic cerebral tissue produced by AII is mediated through AT2 receptors. Abrupt unilateral carotid ligation was performed on 300 gerbils. In five experimental groups, animals received no drug pretreatment: (a) saline; (b)-(d) PD-123319 1.0, 3.0, and 10 mg/kg; and (e) losartan 10 mg/kg. In three additional experimental groups, animals were pretreated with enalaprilat: (f) saline; (g) PD-123319, 10 mg/kg, and (h) losartan, 10 mg/kg. Survival for 48 h was significantly improved by PD-123319 (10 mg/kg) (p < 0.05) and by losartan (10 mg/kg) (p < 0.05) as compared with animals injected with saline. Pretreatment with enalaprilat neutralized the protective effect of losartan. PD-123319 is an AT2 agonist and improved survival in this animal model of stroke. Losartan, an AT1 antagonist, also improved survival, possibly through renin release and AT2 stimulation by endogenous AII. This effect was neutralized by enalaprilat.
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PMID:Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation. 789 77

The rabbit proximal tubule (PT) has been widely utilized to study the direct effects of angiotensin II (ANG II) on PT function. The purpose of the present study was to characterize the binding properties of PT ANG II receptors, using nonpeptide antagonists, and to clone a rabbit PT ANG II receptor. In rat and rabbit kidney cortical brush-border and basolateral membranes, specific binding of 125I-ANG II was inhibited by the AT1 ANG II-receptor antagonist DuP 753, but not by the AT2 antagonist PD 123319. Using a rabbit kidney cortex cDNA library, we isolated cDNA encoding an ANG II receptor, with an open-reading frame sharing a high degree of sequence homology to previously cloned AT1 ANG II receptors. In transfected COS-1 cells, this rabbit ANG II receptor had properties of the AT1 class. Northern analysis revealed high levels of mRNA expression for this receptor in rabbit kidney cortex and adrenal gland. Within the kidney, message was detected in primary cultures of rabbit PT cells, as well as in freshly isolated rabbit PT segments. Message was also present in cells of the mouse PT line, MCT, and in rat glomerular mesangial cells. Utilizing polymerase chain reaction (PCR) with primers derived from the 1st and 4th transmembrane domains of the rat AT1A ANG II receptor, a 279-bp DNA fragment was amplified from reverse-transcribed RNA from rabbit PT cells. This DNA encoded an amino acid sequence identical to that encoded by the rabbit kidney cDNA clone in the corresponding region and differed by a single base substitution. Southern analysis of rabbit genomic DNA restriction digests with the rabbit ANG II receptor probe revealed hybridization to a single band in each lane. These results indicate that an AT1 ANG II receptor is present in the PT and that a single gene codes for the AT1 receptor in rabbit. The clone isolated in the present study should provide a useful tool with which to study the regulation of the PT renin-angiotensin system.
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PMID:Cloning of a rabbit kidney cortex AT1 angiotensin II receptor that is present in proximal tubule epithelium. 791 79

To determine the effect of diabetes on the cardiac renin-angiotensin system, we compared angiotensin II binding density and renin, angiotensinogen, and type 1 angiotensin II (AT1) receptor mRNA levels in hearts of Sprague-Dawley rats 14 days after the administration of streptozotocin (STZ), in vehicle-treated control rats, and in STZ-administered rats made euglycemic with insulin. Myocardial angiotensin II receptor density, determined using an in situ autoradiographic technique, was increased significantly in hyperglycemic diabetic rats in comparison with control rats and euglycemic diabetic rats (P < 0.01) as a result of an increase in both AT1 and AT2 (type 2 angiotensin II) subtypes. The myocardial AT1 receptor mRNA level, determined by slot blot hybridization, was also significantly greater in the hyperglycemic diabetic rats (P < 0.005). Neither plasma renin concentration nor cardiac renin or angiotensinogen mRNA levels differed among the three study groups. In an additional experiment, control and diabetic rats were infused with angiotensin II (200 ng.kg-1.min-1 i.p. for 7 days) or vehicle. Plasma renin concentration decreased significantly, whereas no significant changes occurred in cardiac renin or angiotensinogen steady-state mRNA levels. As in the first experiment, levels of AT1 receptor mRNA were significantly greater in the diabetic rats. Thus, myocardial angiotensin II receptor density is increased in diabetic rats in association with an increase in steady-state AT1 receptor mRNA levels, an abnormality that appears to be independent of changes in the circulating renin-angiotensin system.
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PMID:The cardiac renin-angiotensin system in STZ-induced diabetes. 792 85

There is increasing evidence that an activated intrarenal renin-angiotensin system (RAS) alters renal hemodynamics and fluid balance and that such events may lead to the development of hypertension. To examine the role of the glomerular RAS in the development of hypertension in the spontaneously hypertensive (SHR) rat, we studied angiotensin (ANG) II receptors in isolated glomeruli from young (4- to 5-wk-old) and adult (10- to 12-wk-old) SHR and from age-matched, normotensive Wistar-Kyoto (WKY) rats. Glomerular ANG II receptor density in young SHR is 3-fold higher than in age-matched WKY rats (2033 +/- 154 versus 742 +/- 151 receptors/microns2; p < 0.05) and 1.5-fold higher than in adult SHR and WKY rats (1128 +/- 85 and 1198 +/- 181 receptors/microns2, respectively; p < 0.05). Additional studies demonstrated that the differences in receptor density are not related to disparity in receptor occupancy and that they are also independent of systemic ANG levels. Suppression of RAS by ANG converting enzyme inhibitors resulted in a 3-fold increase in receptor density in young SHR rats and a 4.5-fold increase in young WKY rats; receptor density remained greater in young SHR rats (5915 +/- 318 versus 3358 +/- 234 receptors/microns2, p < 0.05). Furthermore, competitive binding experiments using the nonpeptide ANG II antagonists losartan (AT1) and PD 123319 (AT2) indicate that the greater ANG II receptor density in the young SHR rats represents an increase in the number of a single population of AT1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glomerular losartan (DuP 753)-sensitive angiotensin II receptor density is increased in young spontaneously hypertensive rats. 793 16

New approaches to renin-angiotensin blockade: The successful use of angiotensin converting enzyme (ACE) inhibitors in the treatment of hypertension and congestive heart failure has generated a great deal of research interest in developing new pharmacological approaches to block the renin-angiotensin system. In recent years, several new non-peptide angiotensin II antagonists have been synthesized and some of them are available for experimental and/or clinical investigations. Now that experience with the antagonist losartan is accumulating, it is important to compare the effects, the efficacy and the side effects of this agent with those of ACE inhibitors. Effects of losartan compared with ACE inhibitors: So far, ACE inhibitors and the angiotensin II antagonist losartan appear to have similar systemic and regional hemodynamic effects. The impact of ACE inhibition and angiotensin blockade on the various components of the renin-angiotensin system is also comparable except for a marked increase in plasma angiotensin II levels during angiotensin II blockade. This increase in circulating angiotensin II might theoretically lead to an excessive stimulation of the AT2 receptor subtype, but since the function of this receptor is not known it is impossible to evaluate the implications of this reactive rise. Renal effects of losartan: The renal effects of angiotensin II antagonists are also very similar to those of ACE inhibitors. However, a marked increase in uric acid excretion has been observed with the administration of losartan. This uricosuric effect of losartan might represent a clinical advantage unless a state of urinary supersaturation of undissociated uric acid is achieved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The advantages of angiotensin II antagonism. 796 67

Angiotensin II (ANG II) is a potent vasoconstrictor in isolated human placental cotyledons and may contribute to the regulation of fetoplacental perfusion. We have used quantitative in vitro receptor autoradiography to examine antagonist ((Sar1,Ile8)-[125I]ANG II) and agonist ligand ([125I]ANG II) binding sites in normal-term, preeclamptic and fetal (intrauterine) growth retarded pregnancies. A similar distribution of binding sites was demonstrated using both ligands, localized to blood vessels in placental villi. Binding density was inversely related to vessel size, being significantly greater on microvessels in distal regions of the villous tree than on proximal vessels in main stem villi. Binding sites exhibited the characteristics of the AT1 class of ANG II receptor, ligand binding being sensitive to dithiothreitol, completely inhibited by nonpeptide AT1 antagonists (Losartan, EXP3174 and SKF108566) and not inhibited by the AT2 antagonist (PD123319). Guanine nucleotides also inhibited [125I]ANG II binding and abolished the high affinity component of agonist inhibition of (Ser1,Ile8)-[125I]ANG II binding, indicating G protein coupling. The capacity and affinity of the binding sites were significantly lower in placentae from pregnancies complicated by preeclampsia and intrauterine growth retardation compared to that in normal-term controls. These differences were apparently not due to prior receptor occupancy by endogenous ligand, but may reflect activation of the placental renin-angiotensin system and receptor down-regulation. Locally generated ANG II, acting via AT1 receptors, may contribute to the regulation of fetoplacental blood flow and influence placental perfusion in preeclamptic and growth retarded pregnancies.
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PMID:Angiotensin II (AT1) vascular binding sites in human placentae from normal-term, preeclamptic and growth retarded pregnancies. 796 63

1. The purpose of this study was to investigate angiotensin II (AII) receptors in isolated bovine ovarian follicles and the relationship of their density to follicular concentrations of prorenin, active renin, oestradiol and progesterone. 2. Displacement of [125I]-[Sar1-Ile5-Ile8]-AII binding by the AII receptor antagonists PD 123319 and Losartan (DuP 753) confirmed that follicular AII receptors are of subtype 2 (AT2 receptor). 3. The dissociation constant (Kd) for [Ile5]-AII (human AII) was 0.84 (range 0.51-1.47) nmol/L. The receptor density varied between 90 and 5990 (mean 1640) fmol/mg membrane protein. 4. The follicular AII receptor density correlated positively with follicular diameter (Spearman's rho = 0.518; P < 0.003) and tissue weight (Spearman's rho = 0.636; P < 0.0001), and negatively with the active renin concentration in the follicular wall (Spearman's rho = -0.399; P < 0.02). The AII receptor density did not correlate with the follicular fluid concentrations of prorenin, active renin, oestradiol (E2), progesterone (P4) or the E2/P4 ratio. The follicular fluid concentrations of prorenin correlated negatively with the E2/P4 ratio (Spearman's rho = -0.716; P < 0.0001). 5. The inverse relationship between AII receptor density and the high active renin concentrations in the follicular wall suggests an active regulated tissue renin-angiotensin system. A high AII receptor density is a general feature of large bovine ovarian follicles.
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PMID:Angiotensin II receptor density in bovine ovarian follicles relates to tissue renin and follicular size. 798 76


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