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:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O2-). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or beta-galactosidase (beta-gal) reporter gene (5x10(10) plaque formation units [pfu]/mL), and the effect of transgene expression on O2- and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ETA receptor antagonist ABT-627 (3x10(-8) mol/L), NADPH oxidase inhibitor apocynin (10(-4) mol/L), or dominant negative Rac1 gene transfer. The levels of O2- and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not beta-gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O2- from an ETA receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
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PMID:Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. 1451 26

All components of the renin-angiotensin system are localized in the brain. However, because renin is present in very low concentrations, the mechanism by which angiotensin II is formed in the brain remains unclear. We previously reported the development of 2 transgenic mouse models using sensitive reporters, enhanced green fluorescent protein (eGFP) and beta-galactosidase (beta-Gal), to examine the cellular localization of renin and angiotensinogen in the mouse brain. To determine whether renin and angiotensinogen are coexpressed or present in neighboring cells in the rostral ventrolateral medulla (RVLM) and other cardiovascular control regions of the brain, we produced and examined double-transgenic mice, which express eGFP driven by the renin promoter (REN-1c/eGFP) and beta-gal driven by the human angiotensinogen promoter (hAGT/beta-gal). Using these reporter transgenes as sensitive markers for renin and angiotensinogen expression, we conclude that both proteins are coexpressed in the parabrachial nucleus and central nucleus of the amygdala and are in adjacent cells in the RVLM, reticular formation, bed nucleus of the stria terminalis, subfornical organ, and CA1-3 region. These data suggests that, in these areas, both renin and angiotensinogen are in close proximity providing the potential for the local formation of angiotensin I either intracellularly, when there is colocalization, or in the interstitium, when they are in juxtaposed cells.
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PMID:Adjacent expression of renin and angiotensinogen in the rostral ventrolateral medulla using a dual-reporter transgenic model. 1503 61

To assess the feasibility of using the renin promoter for expressing Cre recombinase in juxtaglomerular (JG) cells only, we generated five independent transgenic mouse lines (designated hRen-Cre) expressing Cre recombinase under control of a 12.2-kb human renin promoter. In the kidneys of adult mice Cre mRNA (RT-PCR) was found in the renal cortex, with Cre protein (immunohistochemistry) being localized in afferent arterioles and to a lower degree in interlobular arteries. Cre mRNA levels were regulated in a renin-typical fashion by changes in oral salt intake, water restriction, or isoproterenol infusion, indicating the presence of key regulatory elements within 12.2 kb of the 5'-flanking region of the human renin gene. hRen-Cre mice were interbred with both the ROSA26-EGFP and ROSA26-lacZ reporter strains to assess renin promoter activity from Cre-mediated excision of a floxed stop cassette and subsequent enhanced green fluorescent protein (EGFP) and beta-galactosidase (beta-gal) detection. In adult mice, beta-gal staining and EGFP were observed in afferent arterioles and interlobular arteries, overlapping with Cre protein expression. In addition, intense beta-gal staining was found in cortical and medullary collecting ducts where Cre expression was minimal. In embryonic kidneys, beta-gal staining was detected in the developing collecting duct system beginning at embryonic day 12, showing substantial activity of the human renin promoter in the branching ureteric bud. Our data indicate that besides its well-known activity in JG cells and renal vessels the human renin promoter is transiently active in the collecting duct system during kidney development, complicating the use of this approach for JG cell-specific excision of floxed targets.
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PMID:Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene. 1641 17

Vascular endothelial cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related cardiovascular disorders, for example, atherosclerosis. Angiotensin II (Ang II), a principal effector of the renin-angiotensin system (RAS), an important signaling molecule involved in atherogenic stimuli, is known to promote aging and cellular senescence. In the present study, induction of Ang II promoted a growth arrest with phenotypic characteristics of cell senescence, such as enlarged cell shapes, increased senescence-associated beta-galactosidase (SA-beta-gal) positive staining cells, and depressed cell proliferation. Ang II drastically decreased the expression level of Bcl-2, in part via the activation of extracellular signal-regulated kinase (ERK). Our results suggest that Ang II can induce HUVEC senescence; one of its molecular mechanisms is a probability that the mitogen-activated protein kinase (MAPK) signal pathway is involved in the process of pathological and physiological senescence of endothelial cells as well as vascular aging.
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PMID:Angiotensin II induces endothelial cell senescence via the activation of mitogen-activated protein kinases. 1838 64

Connexin (Cx) proteins are known to play a role in cell-to-cell communication via intercellular gap junction channels or transiently open hemichannels. Previous studies have identified several connexin isoforms in the juxtaglomerular apparatus (JGA), but the vascular connexin isoform Cx45 has not yet been studied in this region. The present work aimed to identify in detail the localization of Cx45 in the JGA and to suggest a functional role for Cx45 in the kidney using conditions where Cx45 expression or function was altered. Using mice that express lacZ coding DNA under the control of the Cx45 promoter, we observed beta-galactosidase staining in cortical vasculature and glomeruli, with specific localization to the JGA region. Renal vascular localization of Cx45 was further confirmed with the use of conditional Cx45-deficient (Cx45fl/fl:Nestin-Cre) mice, which express enhanced green fluorescence protein (EGFP) instead of Cx45 only in cells that, during development, expressed the intermediate filament nestin. EGFP fluorescence was found in the afferent and efferent arteriole smooth muscle cells, in the renin-producing juxtaglomerular cells, and in the extra- and intraglomerular mesangium. Cx45fl/fl:Nestin-Cre mice exhibited increased renin expression and activity, as well as higher systemic blood pressure. The propagation of mechanically induced calcium waves was slower in cultured vascular smooth muscle cells (VSMCs) from Cx45fl/fl:Nestin-Cre mice and in control VSMC treated with a Cx45 gap mimetic peptide that inhibits Cx45 gap junctional communication. VSMCs allowed the cell-to-cell passage of the gap junction permeable dye Lucifer yellow, and calcium wave propagation was not altered by addition of the ATP receptor blocker suramin, suggesting that Cx45 regulates calcium wave propagation via direct gap junction coupling. In conclusion, the localization of Cx45 to the JGA and functional data from Cx45fl/fl:Nestin-Cre mice suggest that Cx45 is involved in the propagation of JGA vascular signals and in the regulation of renin release and blood pressure.
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PMID:Connexin45 is expressed in the juxtaglomerular apparatus and is involved in the regulation of renin secretion and blood pressure. 1857 50

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR(betageo/+) mice were generated from embryonic stem (ES) cells with a gene trap integration of a beta-galactosidase-neomycin phosphotransferase (betageo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GR(betageo/+) mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GR(betageo/+) mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GR(betageo/+) mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.
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PMID:Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet. 1869 39

Renin plays a critical role in fluid and electrolyte homeostasis by cleaving angiotensinogen to produce Ang peptides. Whilst it has been demonstrated that renin mRNA is expressed in the brain, the distribution of cells responsible for this expression remains uncertain. We have used a transgenic mouse approach in an attempt to address this question. A transgenic mouse, in which a 12.2 kb fragment of the human renin promoter was used to drive expression of Cre-recombinase, was crossed with the ROSA26-lac Z reporter mouse strain. Cre-recombinase mediated excision of the floxed stop cassette resulted in expression of the reporter protein, beta-galactosidase. This study describes the distribution of beta-galactosidase in the brain of the crossed transgenic mouse. In all cases where it was examined the reporter protein was co-localized with the neuronal marker NeuN. An extensive distribution was observed with numerous cells labeled in the somatosensory, insular, piriform and retrosplenial cortices. The motor cortex was devoid of labeled cells. Several other regions were labeled including the parts of the amygdala, periaqueductal gray, lateral parabrachial nucleus and deep cerebellar nuclei. Overall the distribution shows little overlap with those regions that are known to express receptors for the renin-angiotensin system in the adult brain. This transgenic approach, which demonstrates the distribution of cells which have activated the human renin promoter at any time throughout development, yields a unique and extensive distribution of putative renin-expressing neurons. Our observations suggest that renin may have broader actions in the brain and may indicate a potential for interaction with the (pro)renin receptor or production of a ligand for non-AT(1)/AT(2) receptors.
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PMID:Distribution of cells expressing human renin-promoter activity in the brain of a transgenic mouse. 1884 Apr 19

Gap junction channels facilitate chemical and electrical communication between adjacent cells. Gap junction protein, connexin (Cx), is expressed in the endothelial cells of vessels, glomerulus, and renin-secreting cells of the kidney. The purpose of this study was to investigate the role of Cx in renin release using Cx-overexpressing As 4.1 cells. The adenovirus-induced Cx overexpression was conducted by using recombinant adenovirus containing the cDNA encoding Cx37, Cx40, Cx43 (Ad-Cx), and beta-galactosidase (Ad-beta-gal). In 40-overexpressing cells, basal renin release increased in a time-dependent manner but it was significantly lower than that in Ad-beta-gal-treated cells. In Cx37- and Cx43-overexpressing cells, basal renin release was increased in a time-dependent manner, which was not different from control cells. 18-beta glycyrrhetinic acid (GA), a gap junction blocker, stimulated renin release dose-dependently and increased intracellular Ca(2+) in both Cx43-overexpressing cells and control cells. However, no significant differences were observed. An increase in renin release by 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester, a putative antagonist of Ca(2+) release from intracellular sequestration sites, was also similar between two groups. These results suggest that Cx43 may unlikely alter the regulation of renin release and intracellular Ca(2+) by gap junction blocker in As 4.1 cells.
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PMID:Regulation of renin release by connexin 43 in As 4.1 cell line. 2018 75

The renin-angiotensin system is activated in the early phase of two-kidney, one-clip (2K-1C) hypertension. The paraventricular nucleus (PVN) integrates inputs regulating sympathetic outflow. The PVN receives inputs from plasma angiotensin II via projections from circumventricular organs and from renal afferent nerves transmitted via the nucleus tractus solitarii. Nitric oxide within the PVN may exert a sympathoinhibitory effect. These studies tested whether decreasing endogenous nitric oxide by introducing dominant negative (DN) constructs for neuronal nitric oxide synthase (nNOS) into PVN chronically augments hypertension and/or modulates baroreflex function. Male 6-week-old Sprague-Dawley rats underwent sham surgery or right renal artery clipping and placement of radiotelemetry transmitters. One week later, the PVN was injected bilaterally with 250 nl artificial cerebrospinal fluid containing 250 ng microl(-1) of RSV beta-galactosidase (beta-Gal), cytomegalovirus (CMV) wild-type (WT nNOS), or respiratory syncytial virus (RSV) haeme domain or RSV haemeRedF (DN nNOS). Haemodynamics were monitored for 5 weeks. Then left renal nerve electrodes were placed, and 2 days later the rats underwent baroreflex testing in the conscious state. The rise in mean arterial pressure (MAP) was significantly potentiated in the DN nNOS 2K-1C group beyond 15 days after PVN injection. By day 35, MAP in the 2K-1C groups was 152 +/- 6.3 (beta-Gal), 155.1 +/- 6.6 (WT nNOS) and 179 +/- 5.4 mmHg (DN nNOS; P < 0.01 versus all other groups). Sham-clipped rats remained normotensive. All groups displayed progressive bradycardia over time that was attenuated in the DN nNOS 2K-1C group. Baroreflex curves shifted to higher pressures, and baroreflex sensitivity of heart rate was diminished to a similar extent in all groups of 2K-1C rats. The baroreflex response of renal sympathetic nerve activity was preserved. The PVN tissue from DN nNOS rats had decreased dimerization of nNOS and generation of total nitric oxide. These findings indicate that chronic interference of nNOS dimerization required for generation of nitric oxide within the PVN potentiates the increase of blood pressure by modulating the sympathoexcitation that accompanies renovascular hypertension.
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PMID:Neuronal nitric oxide synthase within paraventricular nucleus: blood pressure and baroreflex in two-kidney, one-clip hypertensive rats. 2049 20


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