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)

The angiotensin-converting enzyme 2 (ACE2) is an important regulator of the renin-angiotensin system and was very recently identified as a functional receptor for the SARS virus. The ACE2 sequence is similar (sequence identities 43% and 35%, and similarities 61% and 55%, respectively) to those of the testis-specific form of ACE (tACE) and the Drosophila homolog of ACE (AnCE). The high level of sequence similarity allowed us to build a robust homology model of the ACE2 structure with a root-mean-square deviation from the aligned crystal structures of tACE and AnCE less than 0.5A. A prominent feature of the model is a deep channel on the top of the molecule that contains the catalytic site. Negatively charged ridges surrounding the channel may provide a possible binding site for the positively charged receptor-binding domain (RBD) of the S-glycoprotein, which we recently identified [Biochem. Biophys. Res. Commun. 312 (2003) 1159]. Several distinct patches of hydrophobic residues at the ACE2 surface were noted at close proximity to the charged ridges that could contribute to binding. These results suggest a possible binding region for the SARS-CoV S-glycoprotein on ACE2 and could help in the design of experiments to further elucidate the structure and function of ACE2.
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PMID:A model of the ACE2 structure and function as a SARS-CoV receptor. 1471 71

Cytokines from the interleukin-6 (IL-6) family have been reported to play an important synergistic role with angiotensin II in the development of pathological cardiac hypertrophy. Whether their expression pattern changes in vivo, in an angiotensin I-dependent hypertrophied myocardium has not been reported. In this study, we addressed that issue using two animal models of angiotensin II-dependent cardiac hypertrophy. Heterozygous transgenic TGR(mRen2)27 (TGR) with an overactive cardiac renin angiotensin system and the closely related spontaneously hypertensive rats (SHR) were compared to their respective control rats. The mRNA levels of IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1) as well as their receptor subunits, glycoprotein 130 (gp130), IL-6 receptor (IL-6R), LIFR, and CNTFR, were measured by semi-quantitative RT-PCR. The protein levels of IL-6, LIF and CT-1 were investigated by western blot. TGR and SHR both displayed significant over expression of mRNA and protein levels for IL-6 and LIF. In TGR, the increased level of LIF was accompanied by a decrease in mRNA levels for LIFR and CNTFR. In SHR, a higher level of mRNA IL-6R was observed. By contrast, the mRNA and protein levels for CT-1 and the mRNA level for gp130 did not vary in these two models. These findings suggest that IL-6 and LIF, but not CT-1, contribute to angiotensin II-dependent left ventricular hypertrophy in the two hypertensive rat models, TGR(mRen2)27 and SHR.
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PMID:Increased expression of IL-6 and LIF in the hypertrophied left ventricle of TGR(mRen2)27 and SHR rats. 1578 20

In this study, we evaluated the effect of prostaglandin E2 (PGE2) on renal and hepatic function using an experimental cirrhosis model plus acute liver damage (ALD). Male Wistar rats treated with carbon tetrachloride (CCl4) for 8 weeks were used for the cirrhosis model. Cirrhotic rats were further exposed to an additional acute dose of CCl4 to induce ALD and then treated with PGE2 intramuscularly twice a day for 7 days (200 microg/Kg/day). PGE2 administration started 3 h after the additional dosing of CCl4 and PGE2 effect on hepatorenal function was examined on days 1, 2, 3, and 7. PGE2-treatment ameliorated the decrease in urinary sodium excretion, and normalized serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and plasma renin observed in cirrhotic rats with ALD. In addition, PGE2-treatment decreased mean arterial pressure, glomerular hypercellularity and thickening of the kidney capillary wall, and liver steatosis and cellular necrosis. Also, PGE2 increased the number of regenerative nodules. Finally, PGE2-treatment inhibited the increase in Alpha 1-acid glycoprotein (pAGP), fibrinogen, and Apo A-1 mRNA expression by 83%, 59%, and 77%, respectively. These results suggest that PGE2 administration may decrease the expression of acute phase proteins. In conclusion, PGE2-treatment improved hepatic and renal function and may be useful to down-regulate the acute phase response in cirrhotic rats presenting ALD induced by CCl4.
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PMID:PGE2 alleviates kidney and liver damage, decreases plasma renin activity and acute phase response in cirrhotic rats with acute liver damage. 1581 58

Angiotensin converting enzyme (ACE) is a key enzyme of the renin-angiotensin and kallikrein-kinin systems responsible for the regulation of blood pressure. Recently the new physiological function of ACE has been revealed: the enzyme hydrolyses in vivo the natural peptide (N-AcSer-Asp-Lys-Pro), a negative regulator of hematopoietic stem cell proliferation. Somatic ACE is a single-chain glycoprotein, which contains two highly homologous domains (N- and C-domains, respectively), possessing a zinc-dependent active site. The domains differ in the rate of substrate hydrolysis, interaction with ACE inhibitors and chloride activation profiles. Specific ACE inhibitors used for treatment of hypertension, inhibit both domains, but their dissociation rates of enzyme-inhibitor complex are different. Selective binding of ACE inhibitors to either N- or C-domain may influence their biological effect during treatment. Different functional significance of these domains may be due to some differences in their thee-dimentional structures. X-ray structure of testicular ACE was recently solved and three-dimentional structure of N-domain was modeled. The structural features of domain active sites may be useful for construction of new selective inhibitors.
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PMID:[Angiotensin converting enzyme domain structure and properties]. 1652 20

The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.
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PMID:CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt. 1738 51

Renin is commonly known as a secretory glycoprotein, which is expressed, stored, and secreted in a regulated manner by the kidney. The rat kidney exclusively expresses secretory renin. In this organ, renin regulates glomerular filtration rate, vascular resistance, and sodium reabsorbtion. In the adult rat heart, secretory preprorenin is not expressed. Instead, an alternative renin transcript is expressed that encodes for a previously unrecognized cytosolic renin. The expression of cytosolic but not of secretory renin increases markedly after myocardial infarction, indicating a role specifically for cytosolic renin in postischemic repair processes. In the adrenal gland, secretory renin is expressed and provides the basis for an intra-adrenal angiotensin (ANG) II amplification system. This amplification system reduces the demand for circulating ANGII to stimulate aldosterone production and thus minimizes any detrimental effects of circulating ANGII in other tissues. The adrenal gland additionally expresses cytosolic renin, which is targeted to mitochondria. Adrenal cytosolic renin increases aldosterone production plasma renin independently.
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PMID:Secretory and cytosolic (pro)renin in kidney, heart, and adrenal gland. 1836 80

Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b+ or CD11c+ APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.
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PMID:Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system. 1970 25

CD38 is a type II glycoprotein that is responsible for the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), Ca(2+)-mobilizing second messengers. The activation of hepatic stellate cells (HSCs) is a critical event in hepatic fibrosis because these cells are the main producers of extracellular matrix proteins in the liver. Recent evidence indicates that the renin-angiotensin system plays a major role in liver fibrosis. In this study, we showed that angiotensin II (Ang II) evoked long lasting Ca(2+) rises and induced NAADP or cADPR productions via CD38 in HSCs. Inositol 1,4,5-trisphosphate as well as NAADP-induced initial Ca(2+) transients were prerequisite for the production of cADPR, which was responsible for later sustained Ca(2+) rises in the Ang II-treated HSCs. Ang II-mediated inositol 1,4,5-trisphosphate- and NAADP-stimulated Ca(2+) signals cross-talked in a dependent manner with each other. We also demonstrated that CD38 plays an important role in Ang II-induced proliferation and overproduction of extracellular matrix proteins in HSCs, which were reduced by an antagonistic cADPR analog, 8-bromo-cADPR, or in CD38(-/-) HSCs. Moreover, we presented evidence to implicate CD38 in the bile duct ligation-induced liver fibrogenesis; infiltration of inflammatory cells and expressions of alpha-smooth muscle actin, transforming growth factor-beta1, collagen alphaI(1), and fibronectin were reduced in CD38(-/-) mice compared with those in CD38(+/+) mice. These results demonstrate that CD38-mediated Ca(2+) signals contribute to liver fibrosis via HSCs activation, suggesting that intervention of CD38 activation may help prevent hepatic fibrosis.
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PMID:CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: attenuation of hepatic fibrosis by CD38 ablation. 1991 Apr 64

Uromodulin (UMOD) is a glycoprotein expressed on the luminal surface of the apical membrane of renal tubular epithelial cells forming the thick ascending limb of Henle. Here, UMOD forms filamentous structures probably ensuring water impermeability and the countercurrent gradient. The multidomain structure, cellular topology of UMOD and clinical consequences associated with UMOD dysfunction, however, suggest that it may be involved in other biological processes such as receptor-mediated endocytosis, mechanosensation of urinary flow, Wnt-signaling, cell cycle regulation and planar cell polarity. A specific, but as yet unidentified, protease(s) releases UMOD into the urine, where it probably contributes to colloid osmotic pressure, retards passage of positively charged electrolytes, prevents urinary tract infection and modulates formation of supersaturated salts and their crystals. UMOD expression, biosynthesis and excretion are regulated in a complex manner, and dysregulation is found in a wide range of pathological conditions. It is strongly reduced or absent in cases with mutations in UMOD, renin, HNF1B and other genetic disorders causing autosomal dominant hyperuricemic nephropathy. In contrast, elevated UMOD excretion may be associated with, and thus predictive of, chronic kidney disease. UMOD analysis is therefore of importance in all conditions with renal involvement and may be useful in the proper classification of renal diseases.
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PMID:Uromodulin biology and pathophysiology--an update. 2110 54

The human (pro)renin receptor (hPRR) was displayed on the surface of Bombyx mori nucleopolyhedrovirus (BmNPV) with and without fusion to glycoprotein 64 (GP64) of the BmNPV. hPRR1 is a native hPRR with an additional FLAG peptide sequence inserted between the signal peptide and prorenin-binding domain. hPRR2 has the prorenin-binding domain inserted between amino acid residues (81)Asp and (82)Pro of GP64. hPRR4 has the prorenin-binding domain inserted in (81)Asp and (320)Met of partially deleted GP64. Incorporation of hPRR was confirmed in recombinant BmNPV (rBmNPV) but not in cysteine protease-deleted rBmNPV. hPRR1 was observed in ER, but hPRR2 and hPRR4 were observed around the endoplasmic reticulum (ER) and in its periphery. rBmNPV-hPRR1 and -hPRR2, carrying hPRR1 and hPRR2 respectively, showed binding affinity to human renin, but rBmNPV-hPRR4 did not. The presence of hPRR4 of rBmNPV-hPRR4 was confirmed in western blotting under nonreducing conditions, suggesting that although hPRR4 was incorporated in rBmNPV-hPRR4, it behaved as a non-functional aggregate. This rBmNPV display system can also be used for analyzing a ligand-receptor interaction.
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PMID:Display of the human (pro)renin receptor on Bombyx mori nucleopolyhedrovirus (BmNPV) particles using Bm cells. 2276 73


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