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 mechanism by which anti-renin antibody inhibits renin activity was studied by following the kinetics of the reaction with angiotensinogen or a low molecular weight synthetic substrate, tetradecapeptide (TDP). Two monoclonal antibodies (70 pM) inhibited the production of angiotensin I from angiotensinogen but they differed when hog TDP was used as a substrate. R3-47-10 partially and non-competitively inhibited, whereas R3-36-16 stimulated the activity of renin. This is in contrast to the effects of the synthetic renin inhibitor, CGP 29 287, which competitively inhibits the enzyme activity with both substrates. These antibodies probably bind to the renin molecule on the flap which protects the active cleft. Angiotensinogen may be prevented from entering the cleft due to steric hindrance from bound antibody. However TDP, because of its smaller size may still be able to reach the catalytic site. In addition R3-36-16 might freeze the flap in an open position allowing a greater turnover of TDP whereas R3-47-10 may prevent the flap from fully opening and thereby hinder the reaction of TDP with the active site.
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PMID:Modification of the interaction of human renin with different substrates by monoclonal antibodies. 330 93

The preparations of sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(S)- and -3(R)-[(4-methoxyphenyl)amino]-6-methylheptanoates (7a and 7b) from sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(R)- and -3(S)-hydroxy-6-methylheptanoates (1a and 1b) are described. The key step involves the stereospecific intramolecular displacement via a Mitsunobu reaction for the conversion of a beta-hydroxy hydroxamate to a beta-lactam ring. Compounds 7a and 7b are useful as synthetic intermediates for the preparation of enzyme inhibitors that contain 3(S),4(S)- and 3(R),4(S)-diamino-2,2-difluoro-6-methylheptanoic acid inserts. Angiotensinogen analogues VII and VIII that contain these novel amino analogues of difluorostatine were shown to be inhibitors of the enzyme renin. The alpha,alpha-difluoro-beta-aminodeoxystatine-containing compounds were shown to be weaker inhibitors than the corresponding difluorostatine-containing congeners.
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PMID:alpha,alpha-Difluoro-beta-aminodeoxystatine-containing renin inhibitory peptides. 330 15

The expression of renin and angiotensinogen genes in the human placenta and related tissues has been examined by RNA blot hybridization analysis with specific human complementary DNA (cDNA) probes. Renin mRNA was detectable in the chorion throughout pregnancy and in the hydatidiform moles, but not in the decidua, amnion or myometrium. The relative concentration of renin mRNA in the chorion was at the highest level in early pregnancy and decreased thereafter, while the total amount contained in the whole placenta was at the lowest level in early pregnancy, and increased thereafter, reaching at term about one-sixth of the total renin mRNA in the kidney. Hydatidiform moles had an even higher concentration of renin mRNA than the early chorion. There was no significant difference in either the relative concentration or the total renin mRNA content in the placentae from 4 normal and 4 toxemic pregnancies. Angiotensinogen mRNA was undetectable in any of the placental tissues, hydatidiform moles or myometrium. These results show that renin is synthesized in the placenta, possibly to play some physiological role locally by utilizing angiotensinogen which is abundantly present in the maternal systemic circulation.
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PMID:Expression of renin and angiotensinogen genes in the human placental tissues. 333 23

In the present study we examined the effect of depletion of central nervous system serotonin by 5,7-dihydroxytryptamine on blood pressure in male Wistar rats. We also analyzed the relationship between the serotonergic and renin-angiotensin systems. Blood pressure was determined before and after intracisternal administration of 5,7-dihydroxytryptamine, 200 micrograms in saline with 1 mg/ml ascorbic acid (n = 9). Control rats (n = 8) received intracisternal vehicle. Before sacrifice, blood and cerebrospinal fluid samples were obtained. The brain was dissected in several areas. Serotonin, norepinephrine, angiotensinogen, and reninlike concentrations were determined in the brain parenchyma; angiotensinogen concentration was evaluated in cerebrospinal fluid and plasma samples; plasma renin activity was also measured. Treatment produced a significant decrease in blood pressure (-10 mm Hg; p less than 0.025) and, simultaneously, a high depletion of serotonin stores in the studied central areas (p less than 0.001), except in the cerebral cortex. Reninlike concentration was increased in the medulla oblongata (p less than 0.005) and the brainstem (p less than 0.02) after 5,7-dihydroxytryptamine treatment. Angiotensinogen concentration was decreased in the hypothalamus and elevated in the spinal cord. Angiotensinogen concentration in cerebrospinal fluid, plasma angiotensinogen concentration, and plasma renin activity did not change with treatment. Serotonin concentration in the cerebrospinal fluid remained unchanged, while the 5-hydroxyindoleacetic acid level was diminished (-47%; p less than 0.001). Intracisternal administration of 5,7-dihydroxytryptamine produced a hypotensive effect in normal rats and several modifications of the renin-angiotensin complex, suggesting a relationship between the monoaminergic and peptidergic systems.
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PMID:Effect of central serotonin depletion on blood pressure and the renin system in rats. 334 56

The effects of bilateral nephrectomy or a sham operation on plasma angiotensinogen and on the different kininogens were studied in the rat. Total plasma kininogen was measured by RIA of kinins after trypsin hydrolysis. In addition, the high molecular weight (HMW) kininogen and the low molecular weight (T)-kininogen were specifically quantified by using direct RIAs. Angiotensinogen was measured by RIA of angiotensin I after exhaustion by renin. Three groups of control, nonoperated, bilaterally nephrectomized and sham-operated rats were studied in each experiment. Twenty-four hours after either a bilateral nephrectomy or a sham operation total plasma kininogen was elevated approximately 5 times when compared to control rats. Time course measurements from 0 to 48 h in 3 other groups of control, bilaterally nephrectomized and sham-operated rats demonstrated that kininogen gradually increased at 12, 24, and 48 h after the surgery and that the elevation observed in plasma kininogen appeared to be entirely due to an increase in T-kininogen levels. There was no difference in T-kininogen levels between bilaterally nephrectomized and sham-operated animals. By contrast HMW kininogen was neither influenced by surgery nor by nephrectomy. Angiotensinogen increased more than 8 times in bilaterally nephrectomized rats but displayed only little changes in sham-operated animals. During the course of this experiment it was observed that also in control animals submitted to repeated skin incision and venipuncture for blood sampling at the jugular vein, T-kininogen increased dramatically in plasma, but reached values lower than in sham-operated or bilaterally nephrectomized rats. In a third experiment performed in normal rats it was found that T-kininogen levels were more than 3 times elevated over initial values 24 h after a single blood sampling at the jugular vein. These results indicate that T-kininogen but not HMW kininogen is very sensitive to surgery, perhaps as a result of increased T-kininogen synthesis due to an inflammatory reaction. The T-kininogen might participate in the inflammatory reaction that occurs at the site of tissue injury and in the healing process. As there was no difference in T-kininogen, and in HMW kininogen levels between bilaterally nephrectomized and sham-operated rats, the kidneys do not seem to play an important role in the regulation of plasma kininogens. Angiotensinogen, HMW kininogen, and T-kininogen are therefore regulated separately after nephrectomy or surgery.
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PMID:Differential effects of nephrectomy and surgery on plasma kininogens and angiotensinogen in the rat. 337 Dec 63

The distribution of angiotensinogen-like immunoreactivity in the rat brain was investigated using specific antisera against pure rat plasma angiotensinogen in conjunction with the sensitive streptavidin-biotin peroxidase method. Angiotensinogen antisera were shown by radioimmunoassay and Western blotting to recognize angiotensinogen from both rat plasma and cerebrospinal fluid, and to cross-react with des-AI-angiotensinogen (100%) but not with angiotensin I and II, tetradecapeptide, luteinizing hormone-releasing hormone, rat albumin and angiotensinogen from eight other species. Angiotensinogen-like immunoreactivity was detected throughout the rat brain in both neuroglia and neurons. The highest concentration of neuroglial angiotensinogen-like immunoreactivity was in the hypothalamus and preoptic areas, with moderate to heavy concentrations in the mesencephalon and myelencephalon. The cerebellum demonstrated neuroglial staining in the granular layer and fibre tracts. Very little neuroglial staining was noted in the cerebral cortex or olfactory bulbs. Neuronal immunostaining was observed throughout the globus pallidus and the caudate putamen, in various parts of the thalamus and the supraoptic nucleus of the hypothalamus. In the midbrain moderate immunostaining was observed in periaquaductal central gray, the deep mesencephalic nucleus, the inferior colliculus and in scattered cells in the anterior mesencephalon. In the medulla, neuronal staining was localized to the vestibular nuclei and to other cell bodies mainly in the dorsolateral regions. In the cerebellum, staining was noted mainly in the deeper cerebellar nuclei and in the Purkinje cells. Immunostaining in the cerebral cortex was localized to the cingulate cortex and the primary olfactory cortex. Light staining was present in the endopiriform cortex and in scattered neurons adjacent to the external capsule. In the olfactory bulbs light neuronal staining was mainly associated with the mitral cell layer. The widespread distribution of angiotensinogen-like immunoreactivity supports the view that it is synthesized in the central nervous system and forms part of a brain renin-angiotensin system. In addition, its presence at sites other than those normally associated with the control of blood pressure and fluid and electrolyte homeostasis suggests that its involvement may not be limited to these regulatory functions.
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PMID:Immunocytochemical localization of angiotensinogen in the rat brain. 339 83

The distribution of angiotensinogen containing cells was determined in the brain of rats using immunocytochemistry. Specific angiotensinogen immunoreactivity is demonstrated both in glial cells and neurons throughout the brain, except the neocortical and cerebellar territories. Positive neurons are easily and invariably detected in female brains, and haphazardly in male brain (sex hormone dependent). Angiotensinogen immunoreactivity in male brain neurons can be induced by water deprivation or binephrectomy in some areas and particularly in paraventricular nuclei. Finally, the highest concentrations of positive neurons are found in the anterior and lateral hypothalamus, preoptic area, amygdala and some well known nuclei of the mesencephalon and the brainstem. Our results confirm the wide distribution of angiotensinogen mRNA in the brain reported recently by Lynch et al. (1987). Thus the demonstration of angiotensinogen in neurons and glial cells allows a greater understanding of the biochemical and physiological data in accordance with multiple brain renin angiotensin systems.
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PMID:The renin-angiotensin system in the rat brain. Immunocytochemical localization of angiotensinogen in glial cells and neurons. 341 Jul 45

The cleavage of the angiotensinogen molecule by renin is slow. The rate constant for cleavage of the enzyme-substrate complex, Kcat (turnover number) is lower than usual for enzymes (0.6/s for the homologous human renin reactions and 0.15/s for the homologous mouse renin reaction). Thus each round of catalysis occurs in 1.7 s in the human and 6.7 s in the mouse reaction. The Kcat/Km values (10(4)-10(6) l/mol per s; Km, Michaelis constant) are high and in the range for protein inhibitors. The association constants (Ka) are (10(6)-10(7) l/mol) close to that of inhibitors. The slow rate seems to be favourable since homologous reactions are slower than heterologous. Angiotensinogen is structurally related to alpha1-antitrypsin. We conclude that kinetic as well as structural data indicate that angiotensinogen might be considered a protease inhibitor for renin.
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PMID:Is angiotensinogen a renin inhibitor and not the substrate for renin? 351 48

Components of the renin angiotensin system have been demonstrated in mouse and rat brains. However, local synthesis of renin has not been documented. In this study, we employed mouse submandibular gland renin complementary DNA (pDD-1D2) and rat liver angiotensinogen complementary DNA (pRang3) to examine whether renin and angiotensinogen RNA sequences exist in mouse and rat brain. Angiotensinogen messenger RNA sequences were readily demonstrable in whole rat and mouse brain using Northern blot hybridization analysis. Using large quantities (greater than 100 micrograms) of brain total RNA and the sensitive complementary RNA probe, we were able to detect low levels of renin RNA sequences in the brains of both species. The relatively low concentration of brain renin messenger RNA and high concentration of angiotensinogen messenger RNA raises several interesting questions about the distribution of these two proteins and their relative contribution to activity of the brain renin-angiotensin system. In summary, our data demonstrate the expression of both renin and angiotensinogen genes in mouse and rat brains and provide definitive evidence for an independent endogenous brain renin angiotensin system.
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PMID:Identification of renin and angiotensinogen messenger RNA sequences in mouse and rat brains. 351 52

The effects of long-term hypophysectomy on renin secretion and the renin and drinking responses to isoproterenol were investigated in male rats. Drinking responses to angiotensin II, hypertonic saline, and water deprivation for 24 h were also measured. Plasma renin activity and plasma angiotensin II were variably lower in rats that had been hypophysectomized for 21 days than in intact controls. Angiotensinogen was also reduced, but plasma renin concentration was not. Isoproterenol produced a smaller increase in plasma renin activity in hypophysectomized rats than it did in controls, but with the one dose of isoproterenol that was tested, the increase in plasma renin concentration was comparable in the two groups. However, the drinking responses to isoproterenol were greater in the hypophysectomized rats. The drinking responses produced by infusion of angiotensin II were also greater, but the responses to infusion of hypertonic saline and to 24 h of water deprivation were not. The data suggest that in rats hypophysectomized for 21 days the circumventricular organs that mediate thirst are hyperresponsive to circulating angiotensin II, possibly because the relatively low circulating angiotensin II levels permit the upregulation of angiotensin II receptors in these structures.
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PMID:Effect of hypophysectomy on dipsogenic stimuli: evidence for angiotensin supersensitivity. 352 72


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