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)

Patients with apparent mineralocorticoid excess (AME) have low or absent activity of the enzyme 11 beta OH steroid dehydrogenase (11SD), and inappropriately high intrarenal levels of cortisol resulting in Na+ retention and hypertension. Pseudohypoaldosteronism (PHA), in contrast, is characterized by salt wasting despite hyperaldosteronemia, reflecting low or absent mineralocorticoid receptors (MR). Although AME is presumed to reflect inappropriate cortisol occupancy of MR, several features also suggest inappropriate occupancy of glucocorticoid receptors (GR). To test this possibility, we administered carbenoxolone, which is known to block 11SD, to four patients with PHA, and observed marked mineralocorticoid effects, e.g., antinatriuresis and elevated plasma bicarbonate. To further test the possibility that occupancy of renal GR may induce a classical mineralocorticoid response, we administered the highly specific glucocorticoid RU 28362 to adrenalectomized rats and showed that it has profound antinatriuretic effects. Finally, by selectively blocking MR with RU 28318 or GR with RU 38486, we have shown that corticosterone, the physiologic glucocorticoid in rats, has an antinatriuretic effect in adrenalectomized rats via either MR or GR occupancy. Previous studies have clearly shown that MR are inherently nonselective and have equivalent intrinsic affinity for aldosterone, corticosterone, and cortisol. The present studies suggest that this nonselectivity includes the nuclear response element to which either MR or GR may bind to elicit a mineralocorticoid effect, and further underscore the importance of the enzyme 11SD in the specific mineralocorticoid action of aldosterone.
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PMID:Apparent mineralocorticoid excess, pseudohypoaldosteronism, and urinary electrolyte excretion: toward a redefinition of mineralocorticoid action. 217 62

Aldosterone deficiency is caused by various defects of aldosterone biosynthesis in the adrenal gland or hyporeninism. The most important symptoms are hyponatremia and hyperkalemia. These electrolyte disturbances are also found in pseudohypoaldosteronism. Pseudohypoaldosteronism type I is characterized by insensitivity of the distal nephron for aldosterone. Hyperabsorption of chloride in the distal nephron leads to pseudohypoaldosteronism type II, which is linked with hypertension, whereas blood pressure in the other mentioned disorders is decreased. Renal tubular acidosis, mainly type 4, with impaired production of ammonia due to hyperkalemia, is frequently observed in hypoaldosteronism and both types of pseudohypoaldosteronism as well. The therapeutic regimen is different: low doses of fludrocortisone in hypoaldosteronism, potassium restriction, sodium bicarbonate and loop diuretics in type I of pseudohypoaldosteronism, and sodium restriction and chloruretic diuretics (thiazide) in type II of pseudohypoaldosteronism. In some cases hyperkalemia requires the use of potassium-binding resins.
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PMID:[Primary hypoaldosteronism, pseudo-hypoaldosteronism and distal tubular acidosis]. 638 50

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is a rare Mendelian disorder characterised by end-organ unresponsiveness to mineralocorticoids. Most steroid hormone insensitivity syndromes arise from mutations in the corresponding receptor, but available genetic evidence is against involvement of the mineralocorticoid receptor gene, MLR, in PHA1. A complete genome scan for PHA1 genes was undertaken using homozygosity mapping in 11 consanguineous families. Conclusive evidence of linkage with heterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. The two chromosomal regions harbour genes for subunits of the amiloride-sensitive epithelial sodium channel: SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Liddle's syndrome of hypertension and pseudoaldosteronism has been shown to arise from mutations in SCNN1B and SCNN1G. These results strongly suggest that PHA1 and Liddle's syndrome are allelic variants caused by mutations in genes encoding subunits of this sodium channel. These genes are of broad biological interest both in relation to sodium and water homeostasis in mammals and by virtue of their homology to the mec genes of Caenorhabditis elegans involved in mechanosensitivity and neuronal degeneration.
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PMID:Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping. 882 86

The amiloride-sensitive epithelial sodium channel (ENaC) controls sodium reabsorption in the distal nephron. Its activity is under the control of aldosterone. The genes encoding ENaC have been identified and revealed an heteromultimeric structure of the protein composed of three homologous alpha beta gamma subunits. The role of ENaC in the pathogenesis of hypertension has been demonstrated by complete linkage of the gene encoding the beta and gamma subunits to an autosomal form of salt-sensitive hypertension. Analysis of these genes from patients affected by a sever hypertension (Liddle syndrome) identified mutations in the carboxy-terminus of ENaC subunits causing channel hyperactivity, consistent with increased sodium reabsorption in the distal nephron. Pseudohypoaldosteronism type-1 (PHA-1) represents a hereditary form of salt-loosing nephropathy characterized by hyperkalemia, dehydration and metabolic acidosis. Analysis of genes encoding ENaC subunits in patients affected by PHA-1 identified different types of mutations causing loss of function or a decrease in ENaC channel activity. These studies demonstrated the critical role of ENaC channel in the maintenance salt and extracellular fluid balance, and regulation of blood pressure.
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PMID:The ENaC channel as the primary determinant of two human diseases: Liddle syndrome and pseudohypoaldosteronism. 898 44

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.
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PMID:Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21. 917 36

Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2-6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63-129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [theta] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, straight theta=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date.
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PMID:A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. 1086 38

Aldosterone has crucial role for sodium conservation in the kidney, salivary glands, sweat glands and colon. It exerts its effects via the mineralocorticoid receptor (MR) which belongs to the member of the nuclear receptor superfamily. Recently, genetic disorders have been reported to be caused by gain or loss of function of the MR. The amino acid substitution of the ligand-binding domain(S810L) of the MR resulted in the early-onset hypertension exacerbated by pregnancy. This mutation results in constitutive MR activity and alters receptor specificity for progesterone. Pseudohypoaldosteronism type 1 (PHA1) is characterized by congenital aldosterone resistance of the kidney and/or other mineralocorticoid target tissues, resulting in excessive salt wasting. The heterozygous nonsense or missense mutations were identified in the patients with autosomal dominant PHA1 and a sporadic PHA1. This suggests that the full expression of the MR is necessary for salt conservation.
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PMID:[Genetic disorders caused by gain or loss of function of the mineralocorticoid receptor]. 1185 27

Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disorder of hyperkalemia and hypertension. Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease. WNK1 mutations are believed to increase WNK1 expression; the effect of WNK4 mutations remains unknown. The clinical phenotype of PHAII is opposite to Gitelman syndrome, a disease caused by dysfunction of the thiazide-sensitive Na-Cl cotransporter. We tested the hypothesis that WNK kinases regulate the mammalian thiazide-sensitive Na-Cl cotransporter (NCC). Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC. Coexpression with WNK4 suppressed NCC activity by more than 85%. This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane. Unlike WNK4, WNK1 did not affect NCC activity directly. WNK1, however, completely prevented WNK4 inhibition of NCC. Some WNK4 mutations that cause PHAII retained NCC-inhibiting activity, but the Q562E WNK4 demonstrated diminished activity, suggesting that some PHAII mutations lead to loss of NCC inhibition. Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype. Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis.
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PMID:WNK kinases regulate thiazide-sensitive Na-Cl cotransport. 1267 Oct 41

TWO FORMS: Pseudohypoaldosteronisms (PHA) are characterized by end-organ resistance to aldosterone inducing hyperkalemia and hyperaldosteronism. There are two forms of PHA classified according to the level of blood pressure with either hypotension (Type 1 PHA or PHA 1) or hypertension (Type 2 PHA or PHA 2). PHA 1: The association with hypotension and high renin level (PHA 1) is responsible for type 4 tubular acidosis and should suggest congenital or acquired excessive salt loss. Acquired forms are associated with salt wasting of urinary (nephropathy) or digestive (colon resection + ileostomy) origin. Congenital neonatal forms are either sporadic or autosomal dominant or recessive. Sporadic or autosomal dominant forms are caused by mutations in the mineralocorticoid receptor gene and generally remit with age. Autosomal recessive forms are caused by mutations in the gene encoding the amiloride-sensitive sodium channel and are clinically more severe with pulmonary symptoms. PHA 2: The association of hyperkalemia/hyperaldosteronism with high blood pressure should suggest PHA 2 or Gordon's syndrome, still called familial hyperkalemic hypertension. This form of low-renin hypertension is caused by mutations in the WNK genes (WNK 1 for PHA 2C and WNK 4 for PHA 2B), but other genes located on different loci are also involved. These WNK kinases constitute a new signalisation pathway that would regulate blood pressure and homeostasy of Na+, K+, H+ and Cl- ions.
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PMID:[Pseudo-hypoaldosteronisms]. 1502 8

The renal epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium reabsorption through the distal nephron. ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium channel activity (Liddle's Syndrome and Pseudohypoaldosteronism type 1 associated with contrasting effects on blood pressure). Subtle dysregulation of ENaC however may also be important in essential hypertension - a common condition and a major cause of cardiovascular morbidity and mortality. The epithelial sodium channel is formed from three partly homologous subunits. In this review we deals firstly with current views of structural and functional features of the renal epithelial sodium channel with particular emphasis on mechanisms and processes involved in the control of sodium channel activity at the biochemical and cellular levels. We then focus on genetic aspects with reference to the significance of genetic variation in the sodium channel genes in relation to blood pressure. In particular, we review recent investigations on the potential clinical significance of mutations within the genes encoding ENaC subunits in individuals with high blood pressure. Lastly, we also examine the potential value of pharmacological targeting of the renal epithelial sodium channel with the sodium channel inhibitor amiloride for the treatment of hypertension.
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PMID:The renal epithelial sodium channel: genetic heterogeneity and implications for the treatment of high blood pressure. 1678 51


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