Disease relevance of Hypt

• Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension [1].
• The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II-mediated hypertension [1].
• When Ang II (1 ng/g body weight/min) was infused for 2 weeks, mice developed mild to moderate hypertension [2].
• Absence of the AT2 receptor leads to vascular and renal hypersensitivity to ANG II, including sustained antinatriuresis and hypertension [3].
• Tsukuba hypertensive mice, which carry the human genes for renin and angiotensinogen, show cardiac hypertrophy as well as hypertension due to activation of the renin-angiotensin system (RAS) [4].

Psychiatry related information on Hypt

• CBA mice develop hypertension when placed in complex population cages that facilitate social interactions and competition for territory [5].
• Elevated glucocorticoid levels are associated with many diseases, including age-related depression, hypertension, Alzheimer's disease, and acquired immunodeficiency syndrome [6].
• Epidemiological risk factors include alcohol consumption and smoking: hypertension is a risk factor for rupture [7].
• Spontaneously hypertensive rats are often used as models of attention deficit hyperactivity disorder and to investigate the effects of hypertension on cognitive function [8].
• The roles of stress-induced cardiovascular responses and prejudicial life styles in mediating influences on risk of hypertension are discussed [9].

High impact information on Hypt

• Unfortunately for most individuals, the molecular basis of hypertension is unknown, in part because pathological elevations of blood pressure are the result of abnormal expression of multiple genes [10].
• Insulin resistance plays a key role in the pathogenesis of several human diseases, including diabetes, obesity, hypertension, and cardiovascular diseases [11].
• Elevated levels of crosslinked AT1 dimers were present on monocytes of patients with the common atherogenic risk factor hypertension and correlated with an enhanced angiotensin II-dependent monocyte adhesion to endothelial cells [12].
• This explains the hypertension of PHAII but does not account for the hyperkalemia [13].
• Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal NaCl and K+ handling [13].

Chemical compound and disease context of Hypt

• Mice lacking functional BRS-3 developed a mild obesity, associated with hypertension and impairment of glucose metabolism [14].
• CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity [15].
• Propranolol ameliorates the development of portal-systemic shunting in a chronic murine schistosomiasis model of portal hypertension [16].
• Deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension [17].
• We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus [18].

Biological context of Hypt

• The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes [19].
• In young rats (3 weeks old), rAAV-AS AT1-receptor decreases blood pressure and slows the development of hypertension [20].
• AT2-knockout (AT2KO) mice have a phenotype associated with mild hypertension [21].
• Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney, 1-clip hypertension [22].
• Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4 [23].

Anatomical context of Hypt

• These results suggest that increased activation of central AT-1 receptors, perhaps those located at sites involved in AVP release from the posterior pituitary gland, plays a role in the hypertension in RA+ mice [19].
• Although these studies demonstrated protection from hypertension-induced changes in the heart and large arteries, renal arteries were not studied and follow-up did not extend beyond 6 months of age [24].
• As BP reached its plateau in NT ( approximately 1 week after clip), hypertension began to abate and eventually stabilized at significantly lower levels in NSE-AT(1a) mice despite marked elevations in Ang II levels in brain stem and hypothalamus at these later time points [25].
• Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle [26].
• In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries [27].

Associations of Hypt with chemical compounds

• However, the relative contribution of circulating and tissue-derived AII in causing hypertension in these animals is not known [19].
• Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension [24].
• Altered interactions between AT1 and dopamine receptors may play a role in the pathogenesis of hypertension [28].
• The data provide the mechanistic basis for the cerebrovascular dysregulation induced by Ang II and suggest novel therapeutic strategies to counteract the effects of hypertension on the brain [29].
• Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist [27].

Physical interactions of Hypt

• The cosegregation with hypertension of an impaired D1 receptor regulation of renal sodium transport and the development of elevated systolic and diastolic pressure in mice lacking one or both D1A alleles suggest a causal relationship of the D1A receptor gene with hypertension [30].

Regulatory relationships of Hypt

• CONCLUSIONS: Our results suggested that disturbance of the balance of the AT1 and AT2 receptors could trigger pregnancy induced hypertension [31].
• Genetic AT1A receptor deficiency attenuates cold-induced hypertension [32].
• A novel gene (Cmya3) induced in the heart by angiotensin II-dependent but not salt-dependent hypertension in mice [33].
• In addition, only PAR-1 activation induced hypertension following L-NAME, reflecting concurrent PAR-1-mediated vasoconstriction [34].
• Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension [35].

Other interactions of Hypt

• Chronic production of angiotensin IV in the brain leads to hypertension that is reversible with an angiotensin II AT1 receptor antagonist [36].
• Taken together, our findings suggest that overexpression of 11beta-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS [1].
• Human chymase expression in a mice induces mild hypertension with left ventricular hypertrophy [37].
• Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide [38].
• These data demonstrate that the EP2 receptor mediates arterial dilatation, salt-sensitive hypertension, and also plays an essential part in female fertility [39].

Analytical, diagnostic and therapeutic context of Hypt

• While further experiments need to be done on dose-response relationships and on the cellular mechanisms of these effects, the results show the feasibility of AAV as a vector for antisense inhibition, which may ultimately be used in gene therapy for hypertension [20].
• Antisense inhibition is being developed for the treatment of hypertension, myocardial ischaemia and improved allograft survival in human vascular bypass grafts [40].
• Subsequent progression of this intrarenal process after cessation of treatment suggests an independent process that eventually results in malignant hypertension and early death [24].
• The acceleration of atherosclerosis by polygenic (essential) hypertension is well-characterized in humans; however, the lack of an animal model that simulates human disease hinders the elucidation of pathogenic mechanisms [41].
• These data indicate that PI3Kgamma is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kgamma function might be exploited to improve therapeutic intervention on hypertension [42].

References