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: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated that type 1A angiotensin II (Ang II) receptor (AT1A) is the predominant renal subtype and is upregulated by a low sodium diet. We have now tested the hypothesis that upregulation of AT1A mRNA induced by sodium deficiency is renal specific and is mediated by activation of type 1 Ang II receptor (AT1). Male Wistar rats were divided into four groups (n = 5 each) and treated for 2 weeks with normal sodium diet (0.5%), normal sodium plus 3 mg/kg per day losartan, low sodium diet (0.07%), or low sodium diet plus losartan. At the end of the 2 weeks, body weight and mean arterial pressure were not different among the four groups (P > .05). Plasma renin activity was elevated by losartan treatment, sodium restriction, or the combination of the two versus control (P < .05). Northern blot analysis showed that the ratio of renal AT1A to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was increased by losartan treatment, sodium restriction, or the combination of the two versus control (P < .05). In contrast, the ratio of adrenal AT1A to GAPDH mRNA was increased only by sodium restriction versus three other groups (P < .05). Thus, sodium deficiency increases AT1A mRNA in both kidney and adrenal gland, while Ang II receptor blockade by losartan prevents low sodium-induced AT1A mRNA only in adrenal gland.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Dec
PMID:Distinct mechanisms of upregulation of type 1A angiotensin II receptor gene expression in kidney and adrenal gland. 749 83

Ten years ago, the term "oxidative stress" (sigma -O2) was created to define oxidative damage inflicted to the organism. This definition brings together processes involving reactive oxygen species production and action such as free radical production during univalent reduction of oxygen within mitochondria, activation of NADPH-dependent oxidase system on the membrane surface of neutrophils, flavoprotein-catalyzed redox cycling of xenobiotics and exposure to chemical and physical agents in the environment. Since the discovery of the nitric oxide biosynthetic pathway, the deleterious effects of uncontrolled nitric oxide generation are generally classified as oxidative stress. Indeed, products of the reaction of NO and superoxide lead to oxidants such as peroxinitrite, nitrogen dioxide and hydroxyl radical, which are involved in mechanisms of cell-mediated immune reactions and defence of the intracellular environment against microbiol invasion. However NO can also regulate many biological reactions and signal transduction pathways that lead to a variety of physiological responses such as blood pressure, neurotransmission, platelet aggregation, endothelin generation or smooth muscle cell proliferation. Then the uncontrolled NO production can lead to a variety of physiological and pathophysiological responses similar to a Nitric Oxide Stress: activation of guanylate cyclase and production of cGMP: overstimulation of the inducible L-arginine to L-citrulline and NO pathway by bactericidal endotoxins and cytokines has been shown to promote undesired increases in vasodilatation, which may account for hypotension in septic shock and cytokine therapy. stimulation of auto-ADP-ribosylation and modification of SH-groups of glyceraldehyde-3-phosphate dehydrogenase in a cGMP-independent mechanism: by this way, NO in excess can strongly inhibits this important glycolytic enzyme and reduce the cellular energy production. inhibition of ribonucleotide reductase: extensive inhibition of this key enzyme in DNA synthesis in the presence of large amounts of NO could lead to important antiproliferative effects; inhibition of cytochrome P450-dependent metabolism: in Kupffer cells and hepatocytes, LPS-induced overproduction of NO has been shown to inhibit cytochrome P450-dependent metabolism and to mediate the suppression of hepatic metabolism. Moreover, NO synthetized in the peripheral nervous system is known to mediate nonadrenergic noncholinergic (NANC) neurotransmission. Overstimulation of NO synthases might therefore contribute to pathophysiological states such as: gastrointestinal motility, reflux oesophagitis, asthma, adult respiratory distress syndrome (ARDS) and chronic pulmonary artery hypertension. To these NO-mediated biological functions, one could add the biological effects of NO-derivatives such as N-nitrosocompounds, which act as carcinogenic agents, or C-nitrosocompound which were recently used as "zinc-ejecting" agents to inhibit HIV-1 infectivity of human T-lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Does nitric oxide stress exist?]. 852 Oct 87

Despite use as constitutive protein standards to quantify mRNA, data are limited regarding alteration of cyclophilin or glyceraldehyde-3-phosphate dehydrogenase (G3PDH) in hypertension or angiotensin converting enzyme (ACE) inhibitor treatment. We assessed these standards in 6 month old Wistar-Kyoto rats (WKY, n = 16), compared to age-matched spontaneously hypertensive rats (SHR, n = 14). Additional SHR (n = 8) had received enalapril for 3 to 4 months at evaluation. Left ventricular (LV) and kidney RNA was extracted for dot blot cyclophilin and G3PDH cDNA hybridization. Cyclophilin and G3PDH mRNA densitometries were expressed as a ratio. Cyclophilin/G3PDH for the WKY, untreated SHR, and enalapril SHR were 1.56 +/- 0.33, 1.45 +/- 0.42, and 1.49 +/- 0.51, respectively, for the LV, and 1.52 +/- 0.09, 1.43 +/- 0.22, and 1.38 +/- 0.22, respectively, for the kidney. Differences were not significant. Relative expression of cyclophilin/G3PDH was unaffected by genetic SHR hypertension, or long term enalapril. Thus, either constitutive mRNA may be confidently used to index structural or functional protein responses, at the transcriptional level, in the SHR.
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PMID:Influence of pressure overload and ACE inhibitor therapy on constitutive protein mRNA expression in the spontaneously hypertensive rat. 872 42

Chronic elevations in circulating angiotensin II (AngII) levels produce sustained hypertension and increased intrarenal AngII contents through multiple mechanisms, which may include sustained or increased local production of AngII. This study was designed to test the hypothesis that chronic AngII infusion increases renal angiotensinogen mRNA and protein levels, thus contributing to the increase in intrarenal AngII levels. AngII (80 ng/min) was infused subcutaneously for 13 d into Sprague-Dawley rats, using osmotic minipumps. Control rats underwent sham operations. By day 12, systolic arterial BP increased to 184 +/- 3 mmHg in AngII-treated rats, whereas values for sham-treated rats remained at control levels (125 +/- 1 mmHg). Plasma renin activity was markedly suppressed (0.2 +/- 0.1 versus 5.3 +/- 1.2 ng AngI/ml per h); however, renal AngII contents were significantly increased in AngII-treated rats (273 +/- 29 versus 99 +/- 18 fmol/g). Western blot analyses of plasma and liver protein using a polyclonal anti-angiotensinogen antibody demonstrated two specific immunoreactive bands, at 52 and 64 kD, whereas kidney tissue exhibited one band, at 52 kD. Densitometric analyses demonstrated that AngII infusion did not alter plasma (52- or 64-kD), renal (52-kD), or hepatic (52-kD) angiotensinogen protein levels; however, there was a significant increase in hepatic expression of the highly glycosylated 64-kD angiotensinogen protein, of almost fourfold (densitometric value/control value ratios of 3.79 +/- 1.16 versus 1.00 +/- 0.35). Renal and hepatic expression of angiotensinogen mRNA, which was examined by semiquantitative reverse transcription-PCR, was significantly increased in AngII-treated rats, compared with shamtreated rats (kidney, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 0.82 +/- 0.11 versus 0.58 +/- 0.04; liver, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 2.34 +/- 0.07 versus 1.32 +/- 0.15). These results indicate that increases in circulating AngII levels increase intrarenal angiotensinogen mRNA levels, which may contribute to the sustained renal AngII-generating capacity that paradoxically occurs in AngII-treated hypertensive rats.
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PMID:Expression of angiotensinogen mRNA and protein in angiotensin II-dependent hypertension. 1118 90

The arterial wall is composed of dynamically interacting cellular and acellular components that are necessary for the maintenance of vessel homeostasis. Two extracellular proteins in the vessel wall, elastin and laminin, play important structural roles. We recently established a role for the elastin-laminin receptor (ELR) in mechanotransduction of stretch in cultured vascular smooth muscle (VSM) (Am. J. Physiol.: Heart Circ. Physiol. 280(3) (2001) H1354). We found stretch-mediated signaling by the ELR decreased the expression of the proto-oncogene, c-fos, and subsequent cellular proliferation. However, the role for the ELR in mediating pressure-induced changes in gene expression in intact, isolated resistance vessels is unknown and the goal of this study was to ascertain this possibility. In this study, isolated rat cerebral (approximately 180 microm) and mesenteric (approximately 280 microm) arteries were pressurized to 65 mmHg (baseline) and this pressure was held for 2 h. After this equilibration, pressures were increased to either 80 mmHg (n=6) or 140 mmHg (n=6) for 30 min and transcript levels of c-fos and the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Elevation of pressure in the cerebral arteries decreased the c-fos/GAPDH ratio by 72% in the 140 mmHg group compared to the 80 mmHg control. Importantly, the decrease in c-fos expression was blocked by ELR peptide antagonists (VGVAPG or YIGSR, 10 microM, n=6). In contrast, the decrease in c-fos expression was not observed in the mesenteric resistance arteries. In these vessels, pressure (140 mmHg) increased the c-fos/GAPDH ratio (+68% compared to normotensive control, n=6). To account for the difference between the cerebral and mesenteric vessels, histological analysis of elastin fiber content was performed. Cerebral arteries have greater amounts of loose elastin fibers (fibers outside of the organized elastin laminae) in the tunica media compared to mesenteric arteries. This may explain the opposite stretch-induced responses of c-fos expression in these vessels. Stretch-induced ELR signaling may play a prominent role in vascular adaptations to hypertension in specific organ systems. Our data further suggest that ELR activation may represent a larger component of mechanosensitive signaling in the cerebral circulation than in the mesenteric circulation.
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PMID:Mechanotransduction via the elastin-laminin receptor (ELR) in resistance arteries. 1269 94

In human hypertension (HT) plasma tumor necrosis factor (TNF-alpha) and soluble TNF receptor 2 fragment (sTNF-R2) are increased, and the TNF-R2 gene (TNFRSF1B) has been implicated. Therefore, we measured Tnfr2 mRNA in kidney, adrenal, heart, and aorta from rats with ACTH-induced, corticosterone-induced, and spontaneous HT (SHR), and tested the effect of blockade of TNF-alpha by a recombinant TNF-R2 fragment (huTNFR:Fc) on development of HT in the ACTH model. Tnfr2 mRNA was quantified by real-time polymerase chain reaction, as were internal controls, beta-actin, and glyceraldehyde-3-phosphate dehydrogenase mRNA. The results showed no differences in tissue Tnfr2 mRNA between HT and control rats. The ACTH-induced HT was not affected by huTNFR:Fc coadministration. The findings thus offer no support for altered Tnfr2 expression in the rat models studied.
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PMID:Tumor necrosis factor receptor 2 mRNA in rat models of hypertension. 1287 76

We demonstrated recently that plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, are increased by high salt intake concomitantly with a decrease in plasma levels of NO in human hypertension. We investigated the effect of shear stress on ADMA release in 2 types of cells: transformed human umbilical vein endothelial cells (HUVECs; cell line ECV-304) and HUVECs. Exposure of ECV-304 cells and HUVECs to shear stress with the use of a cone-plate viscometer enhanced gene expression of protein arginine methyltransferase (PRMT-1), ADMA synthase. In HUVECs, the ratio of PRMT-1 to glyceraldehyde 3-phosphate dehydrogenase mRNA was increased by 2-fold by a shear stress of > or =15 dyne/cm2. A dominant-negative mutant of IkappaB kinase alpha and troglitazone at 8 micromol/L, an activator of peroxisome proliferator-activated receptor gamma, abolished the shear stress-induced increase in PRMT-1 gene expression in parallel with the blockade of nuclear factor (NF)-kappaB translocation into the nucleus. The activity of dimethylarginine dimethylaminohydrolase, the degradation enzyme of ADMA, was unchanged after shear stress < or =15 dyne/cm2 and was enhanced by 1.48+/-0.06-fold (P<0.05) by shear stress at 25 dyne/cm2. The release of ADMA was increased by 1.64+/-0.10-fold (P<0.05) by shear stress at 15 dyne/cm2 but was not affected by shear stress at 25 dyne/cm2. These results indicate that shear stress enhances gene expression of PRMT-1 and ADMA release via activation of the NF-kappaB pathway. Shear stress at higher magnitudes facilitates the degradation of ADMA, thus returning ADMA release levels to baseline.
Hypertension 2003 Nov
PMID:Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells. 1455 85

Angiotensin-converting enzyme (ACE) 2, a newly emerging component of the renin-angiotensin system, is presumed to be a counterregulator against ACE in generating and degrading angiotensin II. It remains to be elucidated how mRNA levels of these two genes are quantitatively regulated in the kidney and also what kind of clinicopathological characteristics could influence the gene expressions in humans. Seventy-eight cases of biopsy-proven renal conditions were examined in detail. Total RNA from a small part of each renal cortical biopsy specimen was reverse transcribed, and the resultant cDNA was amplified for ACE, ACE2, and glyceraldehyde-3-phosphate dehydrogenase with a real-time PCR system. Then we investigated the relationship between clinicopathological variables and mRNA levels adjusted for glyceraldehyde-3-phosphate dehydrogenase. Statistically significant correlation was not observed between any clinicopathological variables and either of the gene expressions by pairwise comparison. However, a strong correlation was observed between the gene expressions of ACE and those of ACE2. Moreover, the ACE to ACE2 ratio was significantly higher in subjects with hypertension (HT) than that in subjects without HT. Whereas parameters of renal function, e.g. urinary protein excretion (UPE) and creatinine clearance (Ccr), are not significantly related to the ACE to ACE2 ratio as a whole, the HT status may reflect disease-induced deterioration of renal function. That is, UPE and Ccr of subjects with HT are significantly different from those without HT, in which a significant correlation is also observed between UPE and Ccr. Finally, stepwise regression analysis further revealed that only the HT status is an independent confounding determinant of the ACE to ACE2 ratio among the variables tested. Our data suggest that ACE2 might play an important role in maintaining a balanced status of local renin-angiotensin system synergistically with ACE by counterregulatory effects confounded by the presence of hypertension. Thus, ACE2 may exert pivotal effects on cardiovascular and renal conditions.
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PMID:Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. 1730 61

Abnormal endothelial function plays a pivota role in the pathogenesis of diabetic complications. Due to lack of autoregulation of glucose transport in the presence of high extracellular glucose concentrations, intracellular hyperglycaemia induces a series of metabolic changes that ultimately lead to the genesis of both microvascular complications (the hallmark of chronic hyperglycaemic states) and macrovascular damage. In type 2 diabetes, the abnormalities associated with insulin resistance and the metabolic syndrome phenotype (such as high blood pressure, dyslipidaemia, abnormal levels of circulating adipokines and free fatty acids e.g.) also contribute to accelerate the endothelial damage sustained as a result of chronic exposure to hyperglycaemia. Only recently was a unifying theory proposed to account for the four major abnormal pathways activated by chronic hyperglycaemia and thought to damage the endothelial cell and to trigger the downstream micro- and macrovascular complications associated with diabetes mellitus. This pathophysiological sequence revolves around the metabolic abnormalities triggered as a result of overproduction of superoxide by the mitochondrial electron transport chain and subsequent inhibition of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase by increased activity of nuclear poly(ADP-ribose)polymerase.
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PMID:Diabetes and the endothelium. 1754 90

Regulation of angiotensin II type 1 receptor (AT1R) has a pathophysiological role in hypertension, atherosclerosis and heart failure. We started from an observation that the 3'-untranslated region (3'-UTR) of AT1R mRNA suppressed AT1R translation. Using affinity purification for the separation of 3'-UTR-binding proteins and mass spectrometry for their identification, we describe glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an AT1R 3'-UTR-binding protein. RNA electrophoretic mobility shift analysis with purified GAPDH further demonstrated a direct interaction with the 3'-UTR while GAPDH immunoprecipitation confirmed this interaction with endogenous AT1R mRNA. GAPDH-binding site was mapped to 1-100 of 3'-UTR. GAPDH-bound target mRNAs were identified by expression array hybridization. Analysis of secondary structures shared among GAPDH targets led to the identification of a RNA motif rich in adenines and uracils. Silencing of GAPDH increased the expression of both endogenous and transfected AT1R. Similarly, a decrease in GAPDH expression by H(2)O(2) led to an increased level of AT1R expression. Consistent with GAPDH having a central role in H(2)O(2)-mediated AT1R regulation, both the deletion of GAPDH-binding site and GAPDH overexpression attenuated the effect of H(2)O(2) on AT1R mRNA. Taken together, GAPDH is a translational suppressor of AT1R and mediates the effect of H(2)O(2) on AT1R mRNA.
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PMID:Posttranscriptional regulation of angiotensin II type 1 receptor expression by glyceraldehyde 3-phosphate dehydrogenase. 1924 43


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