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)

A lysosomal storage disease (LSD) results from deficient lysosomal enzyme activity, thus the substrate of the mutant enzyme accumulates in the lysosome, leading to pathology. In many but not all LSDs, the clinically most important mutations compromise the cellular folding of the enzyme, subjecting it to endoplasmic reticulum-associated degradation instead of proper folding and lysosomal trafficking. A small molecule that restores partial mutant enzyme folding, trafficking, and activity would be highly desirable, particularly if one molecule could ameliorate multiple distinct LSDs by virtue of its mechanism of action. Inhibition of L-type Ca2+ channels, using either diltiazem or verapamil-both US Food and Drug Administration-approved hypertension drugs-partially restores N370S and L444P glucocerebrosidase homeostasis in Gaucher patient-derived fibroblasts; the latter mutation is associated with refractory neuropathic disease. Diltiazem structure-activity studies suggest that it is its Ca2+ channel blocker activity that enhances the capacity of the endoplasmic reticulum to fold misfolding-prone proteins, likely by modest up-regulation of a subset of molecular chaperones, including BiP and Hsp40. Importantly, diltiazem and verapamil also partially restore mutant enzyme homeostasis in two other distinct LSDs involving enzymes essential for glycoprotein and heparan sulfate degradation, namely alpha-mannosidosis and type IIIA mucopolysaccharidosis, respectively. Manipulation of calcium homeostasis may represent a general strategy to restore protein homeostasis in multiple LSDs. However, further efforts are required to demonstrate clinical utility and safety.
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PMID:Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis. 1825 60

Estrogen receptor (ER) activation in central autonomic nuclei modulates arterial blood pressure (ABP) and counteracts the deleterious effect of hypertension. We tested the hypothesis that hypertension, in turn, influences the expression and trafficking of gonadal steroid receptors in central cardiovascular circuits. Thus, we examined whether ER- and progestin receptor (PR)-immunoreactivity (ir) are altered in medullary and hypothalamic autonomic areas of cycling rats following chronic infusion of the hypertensive agent, angiotensin II (AngII). After 1 week AngII-infusion, systolic ABP was elevated from 103+/-4 to 172+/-8 mmHg (p<0.05; N=8/group) and all rats were in diestrus (low estrogen). In AngII-infused rats the number of PR-immunoreactive nuclei was reduced (-72%) compared to saline-infused controls also in diestrus (p<0.05). Furthermore, the intensity of ERalpha-ir increased selectively in nuclei (16%) and cytoplasm (21%) of cells in the commissural nucleus of the solitary tract (cNTS; p<0.05) while neither the number nor intensity of ERbeta-labeled cells changed (p>0.05). Following chronic AngII-infusion, electron microscopy showed a higher cytoplasmic-to-nuclear ratio of ERalpha-labeling selectively in tyrosine hydroxylase (TH)-labeled neurons in the cNTS. Furthermore, AngII-infusion increased ERalpha-ir in the cytosol of TH- and non-TH neuronal perikarya and increased the amount of ERalpha-ir associated with endoplasmic reticulum only in TH-containing perikarya. The data suggest that hypertension modulates the expression and subcellular distribution of ERalpha and PR in central autonomic regions involved in blood pressure control. Considering that ERalpha counteracts the central and peripheral effects of AngII, these receptor changes may underlie adaptive responses that protect females from the deleterious effects of hypertension.
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PMID:Angiotensin II-induced hypertension differentially affects estrogen and progestin receptors in central autonomic regulatory areas of female rats. 1853 48

Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor cause familial pulmonary arterial hypertension (PAH). We previously demonstrated that the substitution of cysteine residues in the ligand-binding domain of this receptor prevents receptor trafficking to the cell membrane. Here we demonstrate the potential for chemical chaperones to rescue cell-surface expression of mutant BMPR-II and restore function. HeLa cells were transiently transfected with BMPR-II wild type or mutant (C118W) receptor constructs. Immunolocalization studies confirmed the retention of the cysteine mutant receptor mainly in the endoplasmic reticulum. Co-immunoprecipitation studies of Myc-tagged BMPR-II confirmed that the cysteine-substituted ligand-binding domain mutation, C118W, is able to associate with BMP type I receptors. Furthermore, following treatment with a panel of chemical chaperones (thapsigargin, glycerol or sodium 4-phenylbutyrate), we demonstrated a marked increase in cell-surface expression of mutant C118W BMPR-II by FACS analysis and confocal microscopy. These agents also enhanced the trafficking of wild-type BMPR-II, though to a lesser extent. Increased cell-surface expression of mutant C118W BMPR-II was associated with enhanced Smad1/5 phosphorylation in response to BMPs. These findings demonstrate the potential for rescue of mutant BMPR-II function from the endoplasmic reticulum. For the C118W mutation in the ligand-binding domain of BMPR-II, cell-surface rescue leads to at least partial restoration of BMP signalling. We conclude that enhancement of cell-surface trafficking of mutant and wild-type BMPR-II may have therapeutic potential in familial PAH.
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PMID:Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. 1864 53

Reserpine, a natural product extracted from Rauwolfia serpintina or Rauwolfia vomitoria, is a known dopamine depleter that inhibits several neurotransmitters. Reserpine has been used clinically to control hypertension, schizophrenia, insomnia and insanity. The use of this drug, however, has been limited because of its side effects which include oxidative damage to organs, including the liver. Green tea catechins are potent antioxidants that have the potential to counteract reserpine induced oxidative stress. This study investigated the merits of administering green tea concurrently with reserpine to prevent oxidative hepatic damage in Sprague-Dawely (SD) rats. Reserpine was found to cause hepatic damage, with elevated levels of oxidative stress markers, such as Thiobarbituric Acid Reactive Substances (TBARS), transaminases and cholesterol. Reserpine also induced hepatic ultra-structural damage in the cytoplasmic membrane, nuclear envelope, endoplasmic reticulum (rER), ribosomal stripping and mitochondria. Electron microscopy examination showed revival of liver cells as a result of green tea extract administration to experimental rats.
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PMID:Green tea modulates reserpine toxicity in animal models. 1918 37

We sought to determine whether taurine could specifically protect against coronary artery disease during an atherogenic diet and whether taurine affects the lipid profile, metabolites of methionine, and endothelial atherogenic systems. Rabbits were fed one of the following diets for 4 weeks: (1) control diet; (2) 0.5% cholesterol+1.0% methionine; or (3) 0.5% cholesterol+1.0% methionine+2.5% taurine. Endothelial function was examined, and the left main coronary artery atherosclerosis was quantified by stereology and semiquantitative immunohistochemistry to determine the endothelial expression of proteins related to the NO, renin-angiotensin, endoplasmic reticulum, and oxidative stress systems, as well as apoptosis. Taurine normalized hyperhomocysteinemia (P<0.05) and significantly reduced hypermethioninemia (P<0.05) but not lipidemia. The intima:media ratio was reduced by 28% (P=0.034), and atherosclerosis was reduced by 64% (P=0.012) and endothelial cell apoptosis by 30% (P<0.01). Endothelial cell CCAAT/enhancer binding protein homologous protein was normalized (P<0.05). Taurine failed to improve hyperlipidemia, endothelial function, or endothelial proteins related to the NO, renin-angiotensin, and oxidative stress systems. Taurine reduces left main coronary artery wall pathology associated with decreased plasma total homocysteine, methionine, apoptosis, and normalization of CCAAT/enhancer binding protein homologous protein. These results elucidate the antiapoptotic and antiatherogenic properties of taurine, possibly via normalization of endoplasmic reticulum stress.
Hypertension 2009 Jun
PMID:High dietary taurine reduces apoptosis and atherosclerosis in the left main coronary artery: association with reduced CCAAT/enhancer binding protein homologous protein and total plasma homocysteine but not lipidemia. 1939 54

Childhood obesity has reached epidemic proportions. Obesity is an independent risk factor for the development of end-stage renal disease. Endoplasmic reticulum stress and subsequent activation of the unfolded protein response (UPR) are implicated in the development of adipose tissue dysregulation and type 2 diabetes mellitus in obesity. The present study explored the impact of adolescent-onset obesity on the UPR after obesity-related hypertension and nephropathy, using an ovine model in which obesity was induced by increased food intake and reduced activity. Obese young adults had a higher mean arterial pressure (lean, 89.6+/-1.7 mm Hg versus obese, 101+/-3.0 mm Hg; P<0.01) and greater sensitivity to low physiological doses of angiotensin II. Obesity increased the glomerular area and was associated with activation of the UPR in renal cells with a greater abundance of glucose-regulated protein 78, C/EBP homologous protein, Bax, phosphorylated c-Jun amino-terminal kinase, and activating transcription factor 6 (all P<0.05). In addition, there was a marked upregulation of proinflammatory genes, most notably those involved in macrophage signaling. Reactive oxygen species production and handling were also perturbed in obese adults. Renal endoplasmic reticulum stress was positively correlated with macrophage content (r=0.83; P<0.001), phosphorylated c-Jun amino-terminal kinase (r=0.73; P<0.01), and adiposity (r=0.71; P<0.01). In conclusion, adolescent-onset, obesity-related renal endoplasmic reticulum stress was associated with activation of the UPR, apoptosis, and inflammation, potentially increasing the associated renal damage observed in young adults. The UPR may prove to be a useful therapeutic target for the treatment and prevention of obesity-related nephropathy and associated hypertension, thereby reducing the burden of end-stage renal disease.
Hypertension 2009 Jun
PMID:Impact of early onset obesity and hypertension on the unfolded protein response in renal tissues of juvenile sheep. 1941 48

The (pro)renin receptor [(P)RR] plays a pivotal role in the renin-angiotensin system. Experimental models emphasize the role of (P)RR in organ damage associated with hypertension and diabetes. However, a mutation of the (P)RR gene, resulting in frame deletion of exon 4 [Delta4-(P)RR] is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. We have studied (P)RR expression in mouse brain, as well as the effect of transfection of Delta4-(P)RR on neuronal differentiation of rat neuroendocrine PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed a wide distribution of (P)RR, including in key regions involved in the regulation of blood pressure and body fluid homeostasis. In mouse neurons, the receptor is on the plasma membrane and in synaptic vesicles, and stimulation by renin provokes ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the Golgi and in endoplasmic reticulum and redistributed to neurite projections during NGF-induced differentiation. In contrast, Delta4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Cotransfection of PC-12 cells with (P)RR and Delta4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with Delta4-(P)RR, suggesting that the XLMR and epilepsy phenotype resulted from a dominant-negative effect of Delta4-(P)RR, which coexists with normal transcript in affected males. In conclusion, our results show that (P)RR is expressed in mouse brain and suggest that the XLMR and epilepsy phenotype might result from a dominant-negative effect of the Delta4-(P)RR protein.
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PMID:A role of the (pro)renin receptor in neuronal cell differentiation. 1949 75

Epithelial sodium channel (ENaC) is a heteromultimeric Na(+) channel at the apical membrane in the kidney, colon, and lung. Because ENaC plays a crucial role in regulating Na(+) absorption and extracellular fluid volume, its dysregulation causes severe phenotypes including hypertension, hypokalemia, and airway obstruction. Despite the importance of ENaC, its protein quality control mechanism remains less established. Here we firstly show the role of calreticulin (CRT), a lectin-like molecular chaperone in the endoplasmic reticulum (ER), on the regulation of ENaC. Overexpression and knockdown analyses clearly indicated that CRT positively affects the expression of each ENaC subunit (alpha, beta and gamma). CRT overexpression also up-regulated the cell surface expression of alpha-, beta- and gamma-ENaC. Moreover, we found that CRT directly interacts with each ENaC subunit. Although CRT knockdown did not affect the de novo synthesis of ENaC subunits, CRT overexpression decreased alpha-, beta- and gamma-ENaC expression in the detergent (RIPA)-insoluble fraction, suggesting that CRT enhanced the solubility of ENaC subunits. Consistent with the increased intracellular and cell surface expression of ENaC subunits, increased channel activity of ENaC was also observed upon overexpression of CRT. Our study thus identifies CRT as an ER chaperone that regulates ENaC expression and function.
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PMID:Calreticulin positively regulates the expression and function of epithelial sodium channel. 1979 96

Epidemiological studies show a strong association between low birth weight and hypertension, renal, and cardiovascular disease, especially after catch-up growth. Senescence is an important contributor to the progression of chronic disease. Developmentally programmed premature senescence may be a link among low birth weight, catch-up growth, and adult disease. Low birth weight was induced by feeding pregnant rats a low-protein diet from day 12 of gestation to 10 days postdelivery. Low- and normal-birth-weight male offspring were weaned onto regular or high-calorie diets to enhance catch-up growth. Kidneys and hearts of offspring were analyzed for RNA and protein markers of stress-induced senescence (p16, p21, p53, Rb). Markers of mitochondrial stress (p66Shc) and activation of endoplasmic reticulum protein secretion (Ero1alpha) were analyzed as regulators of reactive oxygen species generation. Reactive oxygen species are known to be associated with premature aging. Senescence markers were not different in low- or normal-birth-weight kidneys at birth. During rapid catch-up growth, p16 and p21 increased significantly in low-birth-weight kidneys and hearts (P < 0.01). Renal p16 levels increased progressively and were significantly higher in low-birth-weight kidneys at 3 and 6 mo (P < or = 0.02). Renal p66Shc and Ero1alpha were significantly higher in low- compared with normal- birth-weight kidneys at 6 mo, suggesting reactive oxygen species generation (P < or = 0.03). Low-birth-weight rats exhibit accelerated senescence in kidneys and hearts after rapid catch-up growth, a likely important link between early growth and subsequent hypertension, renal, and cardiovascular disease.
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PMID:Accelerated senescence in kidneys of low-birth-weight rats after catch-up growth. 1982 76

Intra-abdominal hypertension (IAH) and abdominal compartment syndrome are increasingly observed in patients with severe acute pancreatitis (SAP). The aim of this study was to investigate the effects of IAH on pancreatic histology and ultrastructure in a porcine model. We examined 16 intubated and anesthetized domestic pigs with a mean body weight of 50.6 (SD, 3.8) kg. Using a CO2 pneumoperitoneum, the intra-abdominal pressure was increased to 30 mmHg for an investigation period of 6 or 12 h (each study group n = 6). In the control group, the intra-abdominal pressure remained 3.9 (SD, 5.4) mmHg for 12 h. Additional Ringer's solution was infused to maintain cardiac output at the level of controls. After the observation period, specimens were taken for histological and ultrastructural analysis, and animals were killed. Cardiac output did not change when compared with control. Histologically, mild- to moderate-grade necrosis was observed after 12 h of IAH. In the ultrastructural analysis, leukocyte infiltration and swelling of endothelial cells were found. In the acinar cells of the exocrine pancreas, endoplasmic reticulum was dilated, and necrosis was noticed. Mitochondrial damage manifested as cisternal destruction with formation of large vacuoles. In this porcine model, 6 and 12 h of IAH resulted in light-microscopical and ultrastructural changes comparable to pancreatitis in humans. As SAP is often accompanied by IAH, the finding of the underlying study suggests a vicious cycle in which IAH may worsen pancreatitis. Ultimately, these findings are in favor of a decompression in patients with SAP and IAH.
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PMID:Histomorphologic and ultrastructural lesions of the pancreas in a porcine model of intra-abdominal hypertension. 1994 Aug 13


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