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)

Epidemiological, clinical and experimental evidence indicates an inverse association between Mg(2+) levels (serum and tissue) and blood pressure. Magnesium may influence blood pressure by modulating vascular tone and structure through its effects on numerous biochemical reactions that control vascular contraction/dilation, growth/apoptosis, differentiation and inflammation. Magnesium acts as a calcium channel antagonist, it stimulates production of vasodilator prostacyclins and nitric oxide and it alters vascular responses to vasoactive agonists. Mammalian cells regulate Mg(2+) concentration through specialized influx and efflux transport systems that have only recently been characterized. Magnesium efflux occurs via Na(2+)-dependent and Na(2+)-independent pathways. Mg(2+) influx is controlled by recently cloned transporters including Mrs2p, SLC41A1, SLC41A1, ACDP2, MagT1, TRPM6 and TRPM7. Alterations in some of these systems may contribute to hypomagnesemia and intracellular Mg(2+) deficiency in hypertension. In particular increased Mg(2+) efflux through altered regulation of the vascular Na(+)/Mg(2+) exchanger and decreased Mg(2+) influx due to defective vascular and renal TRPM6/7 expression/activity may be important. This review discusses the role of Mg(2+) in vascular biology and implications in hypertension and focuses on the putative transport systems that control vascular magnesium homeostasis. Much research is still needed to clarify the exact mechanisms of Mg(2+) regulation in the cardiovascular system and the implications of aberrant transcellular Mg(2+) transport in the pathogenesis of cardiovascular disease.
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PMID:Magnesium transport in hypertension. 1802 56

Magnesium may influence blood pressure by modulating vascular tone and structure through its effects on myriad biochemical reactions that control vascular contraction/dilation, growth/apoptosis, differentiation and inflammation. Magnesium acts as a calcium channel antagonist, it stimulates production of vasodilator prostacyclins and nitric oxide and it alters vascular responses to vasoconstrictor agents. Mammalian cells regulate Mg2+ concentration through special transport systems that have only recently been characterized. Magnesium efflux occurs via Na2+-dependent and Na2+-independent pathways. Mg2+ influx is controlled by recently cloned transporters including Mrs2p, SLC41A1, SLC41A2, ACDP2, MagT1, TRPM6 and TRPM7. Alterations in some of these systems may contribute to hypomagnesemia and intracellular Mg2+ deficiency in hypertension and other cardiovascular pathologies. In particular, increased Mg2+ efflux through dysregulation of the vascular Na+/Mg2+ exchanger and decreased Mg2+ influx due to defective vascular and renal TRPM6/7 expression/activity may be important in altered vasomotor tone and consequently in blood pressure regulation. The present review discusses the role of Mg2+ in vascular biology and implications in hypertension and focuses on the putative transport systems that control magnesium homeostasis in the vascular system. Much research is still needed to clarify the exact mechanisms of cardiovascular Mg2+ regulation and the implications of aberrant cellular Mg2+ transport and altered cation status in the pathogenesis of hypertension and other cardiovascular diseases.
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PMID:Vascular biology of magnesium and its transporters in hypertension. 2119 86

A chronic magnesium deficiency may be one of the causes of lifestyle-related diseases such as hypertension and diabetes. Serum Mg2+ concentration is strictly controlled by the reabsorption pathway in the renal tubules, but little is known about how Mg2+ reabsorption is upregulated. We searched for food compounds which can increase the expression levels of Mg2+ transport carriers including transient receptor potential melastatin 6 (TRPM6) channel and cyclin M2 (CNNM2). Sodium citrate (SC) increased the mRNA levels of TRPM6 and CNNM2 in renal tubular epithelial NRK-52E cells. The SC-induced elevation of TRPM6 was inhibited by U0126, a mitogen-activated protein kinase kinase (MEK) inhibitor, but the CNNM2 was not. SC increased the levels of p-ERK1/2 and p-c-Fos, which were inhibited by U0126. SC induced alkalization of culture medium. Both SC and alkalization enhanced Mg2+ influx, which was inhibited by U0126 and introduction of TRPM6 siRNA. The reporter activity of TRPM6 was increased by SC and alkalization, which was suppressed by mutation in an AP-1-binding site. The SC-induced elevation of p-ERK1/2 and p-EGFR was inhibited by diphenylene iodonium, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, and erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. SC did not change the level of acetyl histone H3, but increased the association of c-Fos with the promoter region of TRPM6. These results suggest that SC increases TRPM6 expression and Mg2+ influx mediated by the activation of NADPH oxidase and an EGFR/ERK/c-Fos pathway in the renal tubules.
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PMID:Sodium Citrate Increases Expression and Flux of Mg2+ Transport Carriers Mediated by Activation of MEK/ERK/c-Fos Pathway in Renal Tubular Epithelial Cells. 3024 94

Background: Globally, high blood pressure (BP) is the most important risk factor for cardiovascular disease. Several genome-wide association studies (GWAS) have identified variants associated with BP traits at more than 535 chromosomal loci with genome-wide significance. The post-GWAS challenge is to annotate the most likely causal gene(s) at each locus. Chromosome 10q24.32 is a locus associated with BP that encompasses five genes: CYP17A1, BORCS7, AS3MT, CNNM2, and NT5C2 and warrants investigation to determine the specific gene or genes responsible for the phenotype. Aim: To identify the most likely causal gene(s) associated with BP at the 10q24.32 locus using zebrafish as an animal model. Results: We report significantly higher blood flow, increased arterial pulse, and elevated linear velocity in zebrafish larvae with cnnm2 and nt5c2 knocked down using gene-specific splice modification transcriptional morpholinos, compared with controls. No differences in blood-flow parameters were observed after as3mt, borcs7, or cyp17a1 knockdown. There was no effect on vessel diameter in animals with any of the four genes knocked down. At the molecular level, expression of hypertension markers (crp and ace) was significantly increased in cnnm2 and nt5c2 knockdown larvae. Further, the results obtained by morpholino knockdown were validated using zebrafish knockout (KO) lines with cnnm2 and nt5c2 deficiency, again resulting in higher blood flow, increased arterial pulse, and elevated linear velocity. Analysis of nt5c2a KO larvae demonstrated that lack of this gene resulted in reduced expression of cnnm2a, with reciprocal downregulation of nt5c2a in cnnm2a KO larvae. Staining of whole-blood smears from nt5c2 mutants revealed that KO of this gene might be associated with an acute lymphoblastic leukemia phenotype, consistent with literature reports. Additional experiments were designed based on previous literature on cnnm2a mutant zebrafish revealed impaired renal function, high levels of renin, and significantly increased expression of the ren gene, leading us to hypothesize that the observed elevated blood-flow parameters may be attributable to triggering of the renin-angiotensin-aldosterone signaling pathway. Conclusion: Our zebrafish data establish CNNM2 and NT5C2 as the most likely causal genes at the 10q24.32 BP locus and indicate that they trigger separate downstream mechanistic pathways.
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PMID:Studies in Zebrafish Demonstrate That CNNM2 and NT5C2 Are Most Likely the Causal Genes at the Blood Pressure-Associated Locus on Human Chromosome 10q24.32. 3319 69