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)

All the angiotensin peptides originate from angiotensinogen, a glycoprotein synthesized by several tissues, including the brain and the anterior pituitary. In the rat, immunohistochemistry has been used to localize angiotensinogen in gonadotropes and in uncharacterized cells surrounding sinusoids. Both cell types are capable of secreting angiotensinogen in cell culture; only the gonadotropes contain angiotensin II (AngII) and are capable of secreting it in culture. It has been asserted that the perisinusoidal cells are the only source of angiotensinogen for the generation of AngII by gonadotropes. Our current data favor the existence of a complete intracellular renin-angiotensin system (RAS) in gonadotropes and a separate extracellular system which utilizes the high concentration of angiotensinogen from perisinusoidal cells. Furthermore, we postulate that gonadotrope AngII serves mainly reproductive functions, while the proximity of angiotensinogen-secreting cells to folliculostellate cells, and their access to the intercellular sinusoidal and follicular spaces, places the extracellular RAS in a strategic position to affect pituitary growth and the mediation of acute-phase immune responses. In the rat brain, angiotensinogen is expressed by the 16-18th day of fetal life and by areas generally concerned with vasopressor, electrolyte, and fluid homeostasis. Antisense deoxyoligonucleotides to angiotensinogen mRNA lower blood pressure in hypertensive rats and inhibit in vitro growth of neuroblastoma cells, indicating a significant role for angiotensinogen in mitogenic and homeostatic functions. It is commonly agreed that astrocytes express angiotensinogen. Neuronal angiotensinogen has also been demonstrated by immunohistochemistry, as a secretion from neuronal cell cultures, and by reverse-transcriptase polymerase chain reaction. The fate of secreted astrocytic and neuronal angiotensinogen remains obscure. Angiotensinogen is regulated in a tissue-specific manner with smaller or absent responses observed for brain tissue. By using astrocyte and neuronal cultures the actions on angiotensinogen production of growth hormone, IGF-1, inflammatory lipopolysaccharide, and phorbol ester have been examined. Recent observations show that angiotensinogen is regulated positively or negatively by glucocorticoids and that a positive synergism between cAMP and glucocorticoids exists. On the basis of analogous systems for other proteins, a scheme involving glucocorticoid receptors, CREB, and AP-1 transcription factors is formulated to explain glucocorticoid-cAMP interactions. These transcriptional interactions may form a significant functional link between the RAS and adrenergic mechanisms.
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PMID:Novel perspectives on pituitary and brain angiotensinogen. 910 Dec 59

Angiotensin II (Ang II) is an octapeptide generated by the sequential proteolytic action of renin and angiotensin converting enzyme on the glycoprotein angiotensinogen. While numerous mammalian tissues have been shown to express some or all of the components of the renin-angiotensin system (RAS), the function of most of these tissue RAS remains a matter of conjecture. To test for tissue-specific functions of Ang II and as an alternative to co-expressing all the components of RAS, we have engineered a fusion protein that leads to direct Ang II release within specific tissues. The angiotensin peptide is cleaved from the fusion protein within the secretory pathway by the ubiquitous endoprotease furin and is released from the cell by constitutive secretion. Direct injection of an expression vector encoding such a fusion protein into rat cardiac ventricles results in a highly localized expression of atrial natriuretic peptide mRNA (an angiotensin responsive marker of cardiac hypertrophy), demonstrating the utility of this approach for local targeting of mature peptides to tissues in animal models.
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PMID:Tissue targeting of angiotensin peptides. 914 7

A 47-year-old woman was admitted to our hospital for evaluation of general fatigue and dyspnea. She had been diagnosed with progressive systemic sclerosis (PSS) when she was 39 years of age, on the basis of Raynaud's phenomenon, proximal sclerosis, and pigmentation of the skin. On admission, her blood pressure was 206/128 mmHg. Funduscopy revealed grade III (Keith & Wagener) hypertensive retinopathy. Laboratory data showed positivity for anti-nuclear antibody and anticardiolipin beta 2 glycoprotein I antibody, and the plasma level of renin activity (PRA) was abnormally high. Chest X-ray and UCG revealed massive pericardial effusion. On the second hospital day, she was operated on for pericardiodiaphragmatic fenestration. The volume of pericardial effusion amounted to more than 2000 ml. Post operative malignant hypertension persisted. Laboratory data showed thrombocytopenia, hemolytic anemia, and acute renal failure. We diagnosed scleroderma renal crisis (SRC) associated with antiphospholipid syndrome. Following the initiation of angiotensin converting enzyme inhibitor (ACE-I) combined with calcium antagonist and alpha-one blocker, her blood pressure and PRA decreased. She also had been treated with aspirin 81 mg daily. These therapies were effective in recovering the platelet count and stopped the progression of anemia and renal failure. Although either the finding of large pericardial effusion or SRC is associated with poor prognosis in PSS, this case has had a good clinical course. In this case, the findings suggested that anti-phospholipid antibody may have contributed to the pericarditis and SRC.
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PMID:[A case of scleroderma renal crisis with massive pericardial effusion and positivity on antiphospholipid antibody test]. 965 14

Angiotensin II (ANG II) has been implicated in the hypertrophic and fibrotic responses of the heart and kidney to systemic hypertension. To determine whether these actions of ANG II are related to tissue-specific stimulation of growth factors, we infused adult Sprague-Dawley rats with ANG II at 50 ng/min (low dose), 100 ng/min (high dose), or vehicle for 1 week. Rats receiving vehicle or low-dose ANG II were normotensive with normal plasma aldosterone concentration, whereas rats receiving high-dose ANG II were hypertensive with increased plasma aldosterone. Tissue fibrosis was quantified morphometrically, and messenger RNA (mRNA) for transforming growth factor-beta1 (TGF-beta1) and prepro-epidermal growth factor (EGF) was measured in liver, heart, and renal glomeruli and tubules. In addition, mRNA was determined for clusterin, a glycoprotein expressed in response to tissue injury. Compared to vehicle, low-dose ANG II increased TGF-beta1 expression in glomeruli, tubules, and heart, but not in liver, and increased EGF expression in renal tubules only. High-dose ANG II decreased clusterin expression in liver only. Fibrosis was induced by low- and high-dose ANG II in kidney and heart, but not in liver. We conclude that ANG II selectively stimulates TGF-beta1 mRNA in the heart and kidney, which may contribute to cardiac and renal interstitial fibrosis resulting from activation of the renin-angiotensin system independent of hypertension. By stimulating cellular proliferation, selective stimulation by ANG II of EGF in renal tubules may amplify the effects of TGF-beta1. Suppression of clusterin expression in the liver of hypertensive rats may represent a specific response to high levels of circulating ANG II or a response to hypertensive injury.
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PMID:Tissue-specific regulation of growth factors and clusterin by angiotensin II. 965 31

Human angiotensinogen, the specific substrate of renin, is a heterogeneous glycoprotein constitutively secreted by the liver. Different glycosylation levels may be responsible for its heterogeneity. It contains four putative asparagine-linked glycosylation sites (Asn-X-Ser/Thr). Systematic site-directed mutagenesis (Asn replaced with Gln) of these four sites was undertaken, and 11 (single, double, triple, and quadruple (N-4)) mutants were produced in COS-7 and/or CHO-K1 cells and characterized. All of the sites were N-glycosylated with preferential glycosylation of the Asn14 and the Asn271. The suppression of the Asn14 glycosylation site led to 5 times lower Km and a 10 times lower kcat. Angiotensinogen heterogeneity was much lower for the N-4 mutant protein, which produced a single form at 48 kDa. Pulse-chase experiments showed slight intracellular retention (15%) of the deglycosylated protein after 24 h. Interestingly, the N-4 mutant had a higher catalytic efficiency (kcat/Km = 5.0 versus 1.6 microM-1 . s-1) than the wild-type protein. The thermal stability of the N-4 protein was unaffected by deglycosylation, suggesting that it was correctly folded. This deglycosylated recombinant human angiotensinogen could be of value for x-ray crystallography studies.
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PMID:Role of N-glycosylation in human angiotensinogen. 969 81

A soluble angiotensin (Ang) II-generating enzyme has been purified to homogeneity from the rat mesenteric arterial bed (MAB) perfusate by a combination of gel filtration and affinity chromatographies. The enzyme is a glycoprotein of 28.5 kDa (SDS-PAGE), whose N-terminal sequence is identical with that of the rat pancreatic elastase-2; therefore the enzyme will henceforth be referred to as rat MAB elastase-2. When Ang I was used as the substrate, the enzyme specifically released Ang II and the dipeptide His-Leu (Km=36 microM; Kcat=1530 min-1). The catalytic efficiency (Kcat/Km=42.5 min-1 microM-1) of this reaction was comparable to those of other known Ang I-converting enzymes. The proteolytic specificity of the purified enzyme toward mellitin, oxidized insulin B chain, somatostatin-14 and renin substrate tetradecapeptide suggested that the enzyme-substrate interaction was defined by an extended substrate binding site, typical of elastases-2 of pancreatic origin. According to the sensitivity of the rat MAB elastase-2 to various inhibitors this enzyme could be described as a member of the chymostatin-sensitive group of Ang II-forming serine proteases. The localization and biochemical properties of this enzyme suggest that it might play a role in the regional control of vascular tonus.
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PMID:Purification and substrate specificity of an angiotensin converting elastase-2 from the rat mesenteric arterial bed perfusate. 977 38

Unilateral ureteral obstruction (UUO) induces activation of the renin-angiotensin system and upregulation of transforming growth factor-beta1 (TGF-beta1; a cytokine modulating cellular adhesion and fibrogenesis) and clusterin (a glycoprotein produced in response to cellular injury). This study was designed to examine the regulation of renal TGF-beta1 and clusterin by ANG II in the neonatal rat. Animals were subjected to UUO in the first 2 days of life, and renal TGF-beta1 and clusterin mRNA were measured 3 days later. Rats were divided into treatment groups receiving saline vehicle, ANG, losartan (AT(1) receptor inhibitor), or PD-123319 (AT(2) receptor inhibitor). ANG stimulated renal TGF-beta1 expression via AT(1) receptors, a response similar to that in the adult. In contrast, clusterin expression was stimulated via AT(2) receptors, a response differing from that in the adult, in which ANG inhibits clusterin expression via AT(1) receptors. We speculate that the unique response of the neonatal hydronephrotic kidney to ANG II is due to the preponderance of AT(2) receptors in the developing kidney.
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PMID:Angiotensin stimulates TGF-beta1 and clusterin in the hydronephrotic neonatal rat kidney. 1071 83

Different experimental formulations based on aqueous and oily systems, water miscible solvents, and solid dispersions were investigated for their potential to increase the oral bioavailability (F) of two novel piperidine renin inhibitors (Ro-X1: (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]- 5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol; Ro-X2: (R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4- methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol) in dogs compared to their administration as acidic aqueous solution. The compounds were characterized by a low solubility at pH 7 (Ro-X1: 3 micrograms/ml, Ro-X2: 24 micrograms/ml) and a high lipophilicity (Ro-X1: LogP = 5.7, Ro-X2: LogP = 3.7). For Ro-X1 oil-based vehicles resulted in an improvement in the oral bioavailability compared to the aqueous solution (F = 6 +/- 1.2%) with the best result being achieved with a solution in Capmul (F = 14.6 +/- 3.5%). By contrast, for Ro-X2 the highest bioavailability (F = 27.1 +/- 8.4%) was achieved using an aqueous solution. Computer simulations based on the physicochemical parameters of the compounds only predicted that the fraction of compound absorbed in man should be almost quantitative for Ro-X2 and only about 28% for Ro-X1. These results suggest that other factors such as extensive gut and/or hepatic metabolism as well as exclusion by intestinal transporters such as p-glycoprotein, rather than incomplete solubilization in the gut, are the major reasons for the limited oral bioavailability of both compounds.
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PMID:Preformulation approaches to improve the oral bioavailability of two novel piperidine renin inhibitors in dog. 1223 46

Renin is commonly known as a secretory glycoprotein, which is expressed, stored and released in a regulated manner by the kidney. Besides this, a number of extrarenal tissues, such as adrenal gland and heart express or internalise renin. In the heart a local RAS may exert prohypertrophic, proliferative, antiproliferative or apoptotic properties. The local RAS in kidney, adrenal gland and heart are each unique and their modes of action are distinct. This is due to the expression of different renin transcripts and different intracellular sorting and transport events for renin. In the rat kidney exclusively the commonly known preprorenin is expressed encoding for secretory renin. This is targeted to lysosomes, which become secretory renin granules. The cells of the rat adrenal cortex express preprorenin as well, but this is partially targeted to the regulated secretory pathway. Rat adrenocortical cells additionally express an alternative renin transcript, termed exon1A renin, which encodes for a truncated prorenin that is imported into mitochondria. Its function is not known to date. Interestingly, in the rat heart exclusively the alternative transcript is expressed. Even in hypertrophic hearts or after myocardial infarction, preprorenin remains undetectable. Exon1A renin transcript levels, in contrast, markedly increased after myocardial ischemia. This provides a new molecular basis for a function of locally expressed renin. In addition, there are different pathways of renin internalisation by cardiac cells. A mannose-6-phosphate receptor mediated uptake has been described. We recently described another pathway independently of the mannose-6-phosphate receptor. Such a pathway is apparently of functional significance. Subsequent generation of angiotensins and myocyte hypertrophy and proliferation by prorenin through angiotensin generation has been described.
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PMID:Intracellular sorting of renin: cell type specific differences and their consequences. 1250 54

This minireview is an update of a 1997 review on erythropoietin (EPO) in this journal. EPO is a 30,400-dalton glycoprotein that regulates red cell production. In the human, EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extra-renal EPO are produced by the liver in adult human subjects. EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized. EPO receptor activation induces a JAK2 tyrosine kinase, which leads to tyrosine phosphorylation of the EPO receptor and several proteins. EPO receptor binding leads to intracellular activation of the Ras/mitogen-activated kinase pathway, which is involved with cell proliferation, phosphatidylinositol 3-kinase, and STATS 1, 3, 5A, and 5B transcriptional factors. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO acts synergistically with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) to cause maturation and proliferation of erythroid progenitor cells (primarily colony-forming unit-E). Oxygen-dependent regulation of EPO gene expression is postulated to be controlled by a hypoxia-inducible transcription factor (HIF-1alpha). Hypoxia-inducible EPO production is controlled by a 50-bp hypoxia-inducible enhancer that is approximately 120 bp 3' to the polyadenylation site. Hypoxia signal transduction pathways involve kinases A and C, phospholipase A(2), and transcription factors ATF-1 and CREB-1. A model has been proposed for adenosine activation of EPO production that involves protein kinases A and C and the phospholipase A(2) pathway. Other effects of EPO include a hematocrit-independent, vasoconstriction-dependent hypertension, increased endothelin production, upregulation of tissue renin, change in vascular tissue prostaglandins production, stimulation of angiogenesis, and stimulation of endothelial and vascular smooth muscle cell proliferation. Recombinant human EPO (rHuEPO) is currently being used to treat patients with anemias associated with chronic renal failure, AIDS patients with anemia due to treatment with zidovudine, nonmyeloid malignancies in patients treated with chemotherapeutic agents, perioperative surgical patients, and autologous blood donation. A novel erythropoiesis-stimulating factor (NESP, darbepoetin) has been synthesized and when compared with rHuEPO, NESP has a higher carbohydrate content (52% vs 40%), a longer plasma half-life, the amino acid sequence differs from that of native human EPO at five positions, and has been reported to maintain hemoglobin levels just as effectively in patients with chronic renal failure as rHuEPO at less frequent dosing. The use of rHuEPO and darbepoetin to enhance athletic performance is officially banned by most sports-governing bodies because the excessive erythrocytosis can lead to increased thrombogenicity and can cause deep vein, coronary, and cerebral thromboses.
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PMID:Erythropoietin: physiology and pharmacology update. 1252 67


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