Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In spite of a large body of physiological, biochemical, and recently genetic investigations, the causes of hypertension remain largely unknown. Recognition that hypertension is, in part, genetically determined has motivated studies to identify mutations conferring susceptibility. To date, mutations in at least 10 genes have been shown to alter blood pressure. The majority are rare mutations responsible for various mendelian hyper- and hypotensive syndromes, imparting large quantitative effects. Those causing hypertension are glucocorticoid-remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, and Liddle's syndrome. Conversely, pseudohypoaldosteronism type 1, Bartter's, and Gitelman's syndromes all cause hypotension. In addition, mutations in the angiotensinogen gene are associated with hypertension. All these mutations alter blood pressure through a common pathway, affecting salt and water reabsorption in the kidney. These findings demonstrate the place of molecular genetic approaches in elucidating the underlying determinants of human blood pressure variation and may provide insight into the physiological mechanisms underlying common forms of hypertension.
 ...
PMID:Mutations contributing to human blood pressure variation. 923 56

Several important advances have been made in the pathogenesis of mineralocorticoid induced hypertension. A hybrid gene was found to be responsible for glucocorticoid remediable hypertension. This extra gene contains fragments of 11-beta-hydroxylase and aldosterone synthase. The hybrid gene is the result of an unequal crossing-over of the two genes located in close proximity on chromosome 8, and leads to the production of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxocortisol. These hybrid steroids are also detected in patients with aldosterone producing adenoma but not in patients with hyperaldosteronism due to bilateral adrenal hyperplasia. In Apparent "Mineralocorticoid Excess", inherited as an autosomal recessive disorder, an increased ratio of urinary cortisol metabolite to cortisone is diagnostic. The syndrome is due to a deficiency of the renal enzyme 11-beta-hydroxysteroid dehydrogenase type II, which protects the mineralocorticoid receptor against cortisol that binds to the mineralocorticoid receptor like aldosterone. Liddle's syndrome is a rare entity and due to a constitute activation of an aldosterone dependent protein which triggers the amiloride sensitive sodium channel in the kidney. This results in hypokalemic hypertension with suppressed aldosterone and renin levels.
 ...
PMID:[Mineralocorticoid-induced hypertension]. 924 33

Blood pressure is a quantitative trait that varies along a continuum in the general population and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Family studies and twin studies suggest that about 30% of blood pressure variance is attributable to genetic factors and 50% to environmental factors. Two forms of hypertension transmitted on an autosomal recessive basis have been identified: one is glucocorticoid-suppressible hyperaldosteronism (GSH) and the other is Liddle's syndrome (amiloride-suppressible hyperactivity of the epithelial sodium channel). The molecular basis for these two forms of severe hypertension has recently been elucidated. GSH is due to expression of a chimeric gene produced by fusion of the 11 beta-hydroxylase promoter with the region encoding the enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of ACTH, and can be suppressed by administration of glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption, which can be suppressed by administration of amiloride or triamterene. Apart from these rare genetic defects, a number of susceptibility genes can increase the risk of hypertension in a given environment. Their presence is neither necessary nor sufficient to cause hypertension. The best documented example is the angiotensinogen gene. Angiotensiongen is the substrate of renin, and the renin-angiotensinogen reaction is the first and limiting step in the pathway that leads to production of angiotensin II, a peptide with important effects on blood pressure control and the metabolism of water and sodium. Several studies have demonstrated a link between the angiotensinogen gene and familial hypertension or hypertension of pregnancy. The M235T variant of angiotensinogen is more prevalent among hypertensive than among normotensive subjects in several Caucasian and Japanese populations. The M235T variant is also associated with plasma angiotensinogen elevation, which is potentially responsible for increased production of angiotensin II. In other terms, relationships exist between the angiotensinogen genotype, the intermediate phenotype (i.e., plasma angiotensinogen elevation), and the distal phenomenon (i.e., blood pressure elevation). DNA libraries for the study of hypertension have been set up, and many informative genetic markers distributed along the genome have been identified. Using position cloning techniques, these markers could be used in the search for genetic links between arterial hypertension and a chromosomal locus.
 ...
PMID:Molecular genetics of the renin-angiotensin-aldosterone system in human hypertension. 929 68

Genetic defects in aldosterone biosynthesis and action affect blood pressure and electrolyte homeostasis. Aldosterone synthase deficiency, salt-wasting forms of congenital adrenal hyperplasia, and adrenal hypoplasia congenita all cause aldosterone deficiency, signs of which include hyponatremia, hyperkalemia, hypovolemia, elevated plasma renin activity, and sometimes shock and death. Conversely, the inappropriate regulation of aldosterone synthesis seen in glucocorticoid-suppressible hyperaldosteronism may cause hypokalemia, suppressed plasma renin activity, and hypertension. Similar problems occur when the normal ligand specificity of the aldosterone receptor is lost, as in the syndrome of apparent mineralocorticoid excess due to 11 beta-hydroxysteroid dehydrogenase deficiency. The effects of aldosterone are mediated largely through activation of the epithelial sodium channel, and inactivating or activating mutations of this channel leads to signs of mineralocorticoid deficiency or excess, termed pseudohypoaldosteronism and Liddle's syndrome, respectively.
 ...
PMID:Abnormalities of aldosterone synthesis and action in children. 930 Jan 99

Activity of the epithelial sodium channel (ENaC) is a key determinant of sodium homeostasis and blood pressure. Liddle's syndrome, an inherited form of hypertension, is caused by mutations that delete or alter PY domains in the carboxyl termini of beta or gamma ENaC subunits, leading to increased channel activity. In this study we investigated the mechanism of this effect by analysis of wild-type and mutant ENaC activity in Xenopus oocytes. By inhibiting insertion of new channels into the plasma membrane with brefeldin A, we demonstrate that the half-life of the activity of channels containing Liddle's mutations is markedly prolonged compared with wild-type channels (t1/2 of 30 h in mutant versus 3.6 in wild-type, p < 0.001). We investigated the involvement of clathrin-coated pit-mediated endocytosis by co-expressing a dominant-negative dynamin mutant with wild-type ENaC in oocytes. Expression of this specific inhibitor of endocytosis leads to a large increase in the activity of wild-type channels, demonstrating that normal turnover of this channel is through the clathrin-coated pit pathway. In contrast, co-expression of Liddle's mutations and dynamin mutants leads to no further increase in channel activity, consistent with one of the effects of Liddle's mutations being the loss of endocytosis of these channels. These findings demonstrate the normal mechanism of turnover of ENaC from the cell surface and demonstrate a mechanism that can account for the increased number of channels in the plasma membrane seen in Liddle's syndrome.
 ...
PMID:The activity of the epithelial sodium channel is regulated by clathrin-mediated endocytosis. 932 69

Essential hypertension is a polygenic disease. Various genes responsible for rare monogenic forms of hypertension have been identified in the recent years. These are glucocorticoid remediable aldosteronism (GRA), Liddle's syndrome and apparent mineralocorticoid excess (AME). A fourth form, the Bilginturan syndrome is associated with brachydactyly and resembles essential hypertension. The investigations of the pathomechanisms in these rare diseases can help us to understand common hypertension.
 ...
PMID:[Genetics in hypertension research. What can we learn from it regarding common essential hypertension?]. 944 30

Liddle's syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel beta- or gamma-subunits. These mutations delete or alter a conserved proline-rich amino acid sequence referred to as the PY-motif. We report here a Liddle's syndrome family with a betaArg564X mutation with a premature stop codon deleting the PY-motif of the beta-subunit. This family shows marked phenotypic variation in blood pressure, serum potassium levels, and age of onset of hypertension. Given the similarity with primary hypertension, changes in the C termini of the beta- or gamma-subunits may contribute to the development of primary hypertension or to hypertension associated with diabetic nephropathy. Accordingly, the coding sequences for the cytoplasmic C termini of the beta- and gamma-subunits were screened for mutations with the use of polymerase chain reaction, single-strand conformation polymorphism, and direct DNA sequencing in 105 subjects with primary hypertension and 70 subjects with diabetic nephropathy. One frequent polymorphism was identified, but its frequency did not differ among subjects with primary hypertension, subjects with diabetic nephropathy, or control subjects. Two of the 175 subjects with primary hypertension or diabetic nephropathy showed variants that were not present in 186 control subjects. None of the variants changed the PY-motif sequence. In conclusion, a betaArg564X mutation is the likely cause of Liddle's syndrome in this Swedish family, but it is unlikely that mutations in the beta- and gamma-subunit genes of the epithelial sodium channel play a significant role in the pathogenesis of primary hypertension or diabetic nephropathy.
Hypertension 1998 May
PMID:Mutations and variants of the epithelial sodium channel gene in Liddle's syndrome and primary hypertension. 957 23

Epithelial Na+ channels are expressed widely in absorptive epithelia such as the renal collecting duct and the colon and play a critical role in fluid and electrolyte homeostasis. Recent studies have shown that these channels interact via PY motifs in the C terminals of their alpha, beta, and gamma subunits with the WW domains of the ubiquitin-protein ligase Nedd4. Mutation or deletion of these PY motifs (as occurs, for example, in the heritable form of hypertension known as Liddle's syndrome) leads to increased Na+ channel activity. Thus, binding of Nedd4 by the PY motifs would appear to be part of a physiological control system for down-regulation of Na+ channel activity. The nature of this control system is, however, unknown. In the present paper, we show that Nedd4 mediates the ubiquitin-dependent down-regulation of Na+ channel activity in response to increased intracellular Na+. We further show that Nedd4 operates downstream of Go in this feedback pathway. We find, however, that Nedd4 is not involved in the feedback control of Na+ channels by intracellular anions. Finally, we show that Nedd4 has no influence on Na+ channel activity when the Na+ and anion feedback systems are inactive. We conclude that Nedd4 normally mediates feedback control of epithelial Na+ channels by intracellular Na+, and we suggest that the increased Na+ channel activity observed in Liddle's syndrome is attributable to the loss of this regulatory feedback system.
 ...
PMID:Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. 961 57

Liddle's syndrome is an autosomal dominant form of salt sensitive hypertension caused by mutations in the beta or gamma subunit of the epithelial sodium channel. Systematic mutagenesis studies revealed that a conserved PPPXY sequence (PY motif) of the C-terminus of the alpha, beta, or gamma subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of the beta subunit have been reported to cause Liddle's syndrome. We sequenced the C-termini of the beta and gamma subunits of the epithelial sodium channel in a Japanese family clinically diagnosed as having Liddle's syndrome and found a new missense mutation in the PY motif of the beta subunit, P615S. Expression studies with P615S mutant in Xenopus oocytes resulted in an about 3-fold increase in the amiloride-sensitive sodium current compared to the wild type (p = 0.001). These findings provide further clinical evidence for the hypothesis that a conserved PY motif may be critically important for the regulation of the epithelial sodium channel.
 ...
PMID:A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel. 962 62

A 78-year-old woman with hypertension was hospitalized with acute bronchitis. However, she was also found to have hypernatremia, hypokalemia, and metabolic alkalosis. Detailed examination showed a low plasma renin activity and plasma aldosterone concentration. A provisional diagnosis of Liddle's syndrome was established and the patient was successfully treated with triamterene. Although Liddle's syndrome is generally considered an inherited hypertensive disease found in young people, a review of the literature indicated that muscle weakness is an important clinical finding in elderly patients with this disease. Liddle's syndrome should be considered in the differential diagnosis of hypertension even in elderly individuals.
 ...
PMID:Liddle's syndrome in an elderly woman. 963 Feb


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>