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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monogenic or Mendelian forms of hypertension have ushered in a revolution in our knowledge. If we add information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid-remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension. The latter discovery has elucidated how mutations may modify the receptor sufficiently to allow erstwhile antagonists to have an agonistic action. The epithelial sodium channel (ENaC) has been elucidated. Gain-of-function mutations in the beta and gamma subunits of ENaC cause Liddle's syndrome. Loss-of-function mutations in all 3 subunits of ENaC cause hypotension (pseudohypoaldosteronism type I). Thus, all 3 subunits can be mutated, causing either hyper- or hypotension. Three loci have been described for Gordon's syndrome, pseudohypoaldosteronism type II; 2 members of the WNK (with no ly sine K) serine-threonine kinase family have recently been found to be responsible. Autosomal-dominant hypertension with brachydactyly features normal sodium and renin-angiotensin-aldosterone responses. The gene has been mapped to chromosome 12p. The condition is interesting because it may represent a novel neural form of hypertension. The elucidation of Mendelian blood pressure-regulatory disorders has been a resounding success.
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PMID:Monogenic forms of human hypertension. 1189 1

Hypertension is a substantial public health problem affecting about 25% of the population in industrialized societies. The disorder is responsible for many common causes of morbidity and mortality. Despite the important role of hypertension as a cause of disease, its pathogenesis remains largely unknown. The application of genetic approaches to rare monogenic (Mendelian) forms of hypertension and hypotension has begun to delineate molecular pathways underlying human blood pressure variation, defining disease pathogenesis and identifying targets for therapeutic intervention. In all cases the pathophysiology is altered net renal salt reabsorption. Mutations are either affecting circulating mineralocorticoid hormones or renal ion channels and transporters. Examples are glucocorticoid-remediable aldosteronism (GRA), Liddle's syndrome, the syndrome of hypertension exacerbated in pregnancy, and apparent mineralocorticoid-excess (AME). Recently, alterations in genes of a novel serine-threonine kinase family (WNK1 and WNK4) were identified causing pseudohypoaldosteronism type II. The molecular pathway of this syndrome remains unclear. Additionally, there is the syndrome of hypertension associated with brachydactyly type E (Bilginturan's syndrome), for which the molecular mechanism has yet to be identified.
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PMID:The molecular basis of hypertension. 1240 28

A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. 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. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.
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PMID:WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. 1464 84

WNK1 is a serine-threonine kinase, the expression of which is affected in pseudohypoaldosteronism type II, a Mendelian form of arterial hypertension. We characterized human WNK1 transcripts to determine the molecular mechanisms governing WNK1 expression. We report the presence of two promoters generating two WNK1 isoforms with a complete kinase domain. Further variations are achieved by the use of two polyadenylation sites and tissue-specific splicing. We also determined the structure of a kidney-specific isoform regulated by a third promoter and starting at a novel exon. This transcript is kinase defective and has a predominant expression in the kidney compared to the other WNK1 isoforms, with, furthermore, a highly restricted expression profile in the distal convoluted tubule. We confirmed that the ubiquitous and kidney-specific promoters are functional in several cells lines and identified core promoters and regulatory elements. In particular, a strong enhancer element upstream from the kidney-specific exon seems specific to renal epithelial cells. Thus, control of human WNK1 gene expression of kinase-active or -deficient isoforms is mediated predominantly through the use of multiple transcription initiation sites and tissue-specific regulatory elements.
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PMID:Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform. 1464 31

Mutations in the serine-threonine kinase WNK4 [with no lysine (K) 4] cause pseudohypoaldosteronism type II, a Mendelian disease featuring hypertension with hyperkalemia. In the kidney, WNK4 regulates the balance between NaCl reabsorption and K(+) secretion via variable inhibition of the thiazide-sensistive NaCl cotransporter and the K(+) channel ROMK. We now demonstrate expression of WNK4 mRNA and protein outside the kidney. In extrarenal tissues, WNK4 is found almost exclusively in polarized epithelia, variably associating with tight junctions, lateral membranes, and cytoplasm. Epithelia expressing WNK4 include sweat ducts, colonic crypts, pancreatic ducts, bile ducts, and epididymis. WNK4 is also expressed in the specialized endothelium of the blood-brain barrier. These epithelia and endothelium all play important roles in Cl(-) transport. Because WNK4 is known to regulate renal Cl(-) handling, we tested WNK4's effect on the activity of mediators of epithelial Cl(-) flux whose extrarenal expression overlaps with WNK4. WNK4 proved to be a potent inhibitor of the activity of both the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) and the Cl(-)/base exchanger SLC26A6 (CFEX) (>95% inhibition of NKCC1-mediated (86)Rb influx, P < 0.001; >80% inhibition of CFEX-mediated [(14)C] formate uptake, P < 0.001), mediators of Cl(-) flux across basolateral and apical membranes, respectively. In contrast, WNK4 showed no inhibition of pendrin, a related Cl(-)/base exchanger. These findings indicate a general role for WNK4 in the regulation of electrolyte flux in diverse epithelia. Moreover, they reveal that WNK4 regulates the activities of a diverse group of structurally unrelated ion channels, cotransporters, and exchangers.
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PMID:WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia. 1476 28

A polymorphism in intron 10 of the serine-threonine kinase with no lysine (K) 4 gene WNK4 (G-->A, base 1156666 on chromosome 17) has recently been associated with essential hypertension in a white American population. We have attempted to replicate this finding in a well characterized cohort of 184 unrelated hypertensive Australians of British extraction in which biological power was enhanced by them each having 2 hypertensive parents. Controls were 219 normotensive ethnically matched subjects whose parents were both normotensive. Genotyping was performed using the homogeneous MassEXTEND Assay. This showed a frequency of 0.10 for the minor allele in each group (P=0.88). Moreover, blood pressure, body mass index, sex, and plasma lipid levels were similar across genotypes. In conclusion, our study provides no support for an association of the intron 10 variant of WNK4 with essential hypertension in the Anglo-Australian population studied.
Hypertension 2004 Apr
PMID:WNK4 intron 10 polymorphism is not associated with hypertension. 1496 40

Vasoconstrictor factors, like urotensin, angiotensin and catecholamines, activate Rho-dependent serine-threonine kinase (Rho-kinase) and inhibition of this pathway represents a novel therapy for cardiovascular diseases with hypertensive syndrome. The disbalance of relaxing endothelial nitric oxide (NO)-producing and vasoconstrictive pathways can be especially important in diseases where hypertension is accompanied by endothelial dysfunction that compromises NO generation. However, a recent study reported that the efficacy of the Rho-kinase inhibitor (R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide (Y27632) is dramatically attenuated upon removal of endothelium or inhibition of endothelial NO synthase (eNOS). This raises the question whether Rho-kinase inhibition could be an effective treatment in case of hypertension associated with endothelial dysfunction. The purpose of the present study was to determine whether the vasorelaxing effect of Rho-kinase inhibition is mediated through eNOS-dependent mechanisms. We show here that in the models of genetically reduced endothelial NO production (eNOS-/- mice and spontaneous hypertensive rats (SHR)) or in models of pharmacologically reduced endogenous NO production (N(omega)-nitro-L-arginine methyl ester (LNAME) treatment), Rho-kinase inhibition induced a strong vasodilation and reduction of blood pressure indicating independence of Rho-kinase pathway from eNOS. An additional important finding of our study is that Rho-kinase inhibitors induce a strong vasorelaxation and blood pressure reduction upon intravenous injection not only in hypertensive but in normotensive animals, as well. Inhibition of Rho-kinase represents a promising possibility to treat hypertension that is accompanied by endothelial dysfunction.
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PMID:Inhibition of Rho-kinase stimulates nitric oxide-independent vasorelaxation. 1565 8

Mendelian forms of hypertension have ushered in a revolution in our knowledge of blood pressure and volume regulation. If we include information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension. The latter discovery has elucidated how mutations may modify the receptor sufficiently to allow erstwhile antagonists to have an agonistic action. The epithelial sodium channel (ENaC) has been elucidated. Gain-of-function mutations in the beta and gamma subunits of ENaC cause Liddle's syndrome. Loss-of-function mutations in all three subunits of ENaC cause hypotension (pseudohypoaldosteronism type I). Thus, all three subunits can be mutated, causing either hyper or hypotension. Three loci have been described for Gordon's syndrome, pseudohypoaldosteronism type II. Two members of the WNK serine-threonine kinase family have recently been found to be responsible. Their function has been largely elucidated. Autosomal dominant hypertension with brachydactyly features normal sodium and renin-angiotensin-aldosterone responses. The gene has been mapped to chromosome 12p. The condition is interesting because it may represent a novel neural form of hypertension. Finally, at least 5 different genes have been described that when mutated can cause pheochromocytoma. Thus, the elucidation of Mendelian blood pressure-regulatory disorders has been a resounding success.
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PMID:Mendelian forms of human hypertension and mechanisms of disease. 1593 22

The serine-threonine kinase WNK3 modulates Cl- transport into and out of cells through its regulation of SLC12A cation/Cl- cotransporters, implicating it as (one of) the long-sought Cl-/volume-sensitive kinase(s). Integrators in homeostatic systems regulate structurally diverse but functionally coupled elements. For example, the related kinase WNK4 regulates the Na-Cl co-transporter (NCC), paracellular Cl- flux, and the K+ channel ROMK1 (Kir1.1) to maintain renal NaCl and K+ homeostasis; mutations in PRKWNK4, encoding WNK4, cause a Mendelian disease featuring hypertension and hyperkalemia. It is known that WNK3 is expressed in the nephron's distal convoluted tubule (DCT) and stimulates NCC activity. Here, we show that WNK3 is also expressed in cortical and outer medullary collecting duct principal cells. Accordingly, we tested WNK3's effect on the mediators of NaCl and K+ handling in these nephron segments--the epithelial sodium channel (ENaC), paracellular Cl- flux, and ROMK1--using established model systems. WNK3 did not alter paracellular Cl- flux in tetracycline-responsive MDCK II cells, nor affect amiloride-sensitive currents when co-expressed with ENaC in Xenopus laevis oocytes. However, additional co-expression studies in oocytes revealed WNK3 inhibited the renal-specific K+ channel ROMK1 activity greater than 5.5-fold (p < .0001) by altering its plasmalemmal surface expression; WNK3 did not affect ROMK1's conductance or open/closed probability. In contrast, WNK3 had no effect on the activity of the cardiac long-QT syndrome K+ channel KCNQ1/KCNE1 when co-expressed in oocytes. Inhibition of ROMK1 is independent of WNK3's catalytic activity and is mediated by WNK3's carboxyl terminus--a mechanism distinct from its known kinase-dependent activation of NCC. A kinase-inactivating point mutation, or a missense mutation homologous to one in WNK4 that causes disease produced a gain-of-function effect, enhancing WNK3's inhibition of ROMK1 greater than 2.5-fold relative to wild type kinase (p < .0001). The magnitude and specificity of WNK3's effects at both NCC and ROMK1, its co-expression with its targets in the distal nephron, and the established in vivo effect of WNK4 at these same targets provide evidence that WNK3's action is physiologically relevant. WNK3 is likely a component of one of the mechanisms that determines the balance between renal NaCl reabsorption and K+ secretion.
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PMID:WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1). 1635 11

Precise control of cellular Cl(-) transport is necessary for many fundamental physiological processes. For example, the intracellular concentration of Cl(-), fine-tuned through the coordinated action of cellular Cl(-) influx and efflux mechanisms, determines whether a neuron's response to GABA is excitatory or inhibitory. In epithelia, synchrony between apical and basolateral Cl(-) flux, and transcellular and paracellular Cl(-) transport, is necessary for efficient transepithelial Cl(-) reabsorption or secretion. In cells throughout the body, coordination of Cl(-) entry and exit mechanisms help defend against changes in cell volume. The Na-K-Cl and K-Cl cotransporters of the SLC12 gene family are important molecular determinants of Cl(-) entry and exit, respectively, in these systems. The WNK serine-threonine kinase family, members of which are mutated in an inherited form of human hypertension, are components of a signaling pathway that coordinates Cl(-) influx and efflux through SLC12 cotransporters to dynamically regulate intracellular Cl(-) activity.
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PMID:WNK protein kinases modulate cellular Cl- flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters. 1699 Apr 53


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