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)

The WNK kinases are a small group of serine/threonine kinases with unique catalytic domains that lack the lysine residue used in other kinases to co-ordinate ATP (hence, With No K [WNK]). Their closest homologues are found within the mitogen-activated protein kinase (MAPK) pathway suggesting a role in signalling. Two WNK isoforms, WNK1 and WNK4, have been identified as the disease genes for a rare monogenic hypertension syndrome (Gordon's syndrome or pseudohypoaldosteronism type 2 [PHA2]) implicating them in salt homeostasis by the kidney. This is supported by recent data showing widespread expression of WNK1 and WNK4 in mammalian transporting epithelia. Within the kidney, WNKs probably regulate the surface expression of several proteins involved in ion transport, including the sodium-chloride cotransporter (NCCT) and the potassium channel renal outer medullary potassium channel (ROMK), based on co-expression studies in Xenopus oocytes. WNKs, especially WNK4, have been suggested as candidate genes for essential hypertension itself, but evidence for this is lacking. Some of the effects of the WNKs are independent of their kinase function, suggesting that they are dependent on specific protein-protein interactions. It seems likely that the WNKs are part of much larger protein scaffolds in cells and have effects in cells beyond ion transport. However, because of their effect on expression of the NCCT they are attractive drug targets for the development of novel antihypertensive agents. These agents could potentially offer the efficacy of a thiazide diuretic, but without the metabolic side effects usually seen with this class of antihypertensive therapy.
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PMID:WNK kinases and the control of blood pressure. 1586 21

WNKs are large serine/threonine protein kinases structurally distinct from all other members of the protein kinase superfamily. Of the four human WNK family members, WNK1 and WNK4 have been linked to a hereditary form of hypertension, pseudohypoaldosteronism type II. We characterized the biochemical properties and regulation of WNK1 that may contribute to its physiological activities and abnormal function in disease. We showed that WNK1 is activated by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines. In addition, hypotonic stress also led to a modest increase in WNK1 activity. Gel filtration suggested that WNK1 exists as a tetramer, and yeast two-hybrid data showed that the N terminus of WNK1 (residues 1-222) interacts with residues 481-660, which includes the WNK1 autoinhibitory domain and a C-terminal coiled-coil domain. Although cell biological studies have suggested a functional interaction between WNK1 and WNK4, we found no evidence of stable interactions between these kinases. However, WNK1 phosphorylated both WNK4 and WNK2. In addition, the WNK1 autoinhibitory domain inhibited the catalytic activity of these WNKs. These findings suggest potential mechanisms for interconnected regulation of WNK family members.
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PMID:Properties of WNK1 and implications for other family members. 1588 53

Oxidative stress has been implicated in pancreatic beta-cell damage, insulin resistance and vascular function in diabetic patients and the dysfunction of antioxidant enzymes may be associated with the pathogenesis of diabetes. Extracellular superoxide dismutase (EC-SOD) is found in the extracellular matrix of tissues and the major scavenger of superoxide radical. To investigate the role of genetic variability for the pathogenesis of type 2 diabetes, we scanned the protein coding exon and flanking introns of EC-SOD gene for mutation in Japanese type 2 diabetic patients. We identified two missense mutations, Ala40Thr (GCG-->ACG) and Arg213Gly (CGG-->GGG), and a silent mutation, Leu53Leu (CTG-->TTG). For one of these variants, the Ala40Thr polymorphism, the frequency of Thr allele and the number of subjects with Thr allele (Ala/Thr+Thr/Thr) were higher in type 2 diabetic patients (n=205) than those in non-diabetic subjects (n=220) (33.2% versus 24.1%, p=0.003 and 55.6% versus 42.7%, p=0.008, respectively). The patients with Thr allele also showed earlier age at diagnosis of diabetes (42.2+/-7.8 years versus 44.4+/-6.9 years, p=0.037) and higher prevalence of hypertension (53.5% versus 38.5%, p=0.032) than those without the allele. Insulin sensitivity, furthermore, was evaluated in 71 type 2 diabetic patients with short insulin tolerance test (SITT). The patients with Thr allele showed lower insulin sensitivity (Kitt value of SITT) than those without the allele (1.78+/-0.78%/min versus 2.33+/-1.02%/min, p=0.012), although no significant differences in other clinical and biochemical characteristics were observed between two groups. These results suggest that the genetic variant of EC-SOD gene is associated with insulin resistance and the susceptibility to type 2 diabetes.
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PMID:Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes. 1599 Jan 93

WNK (with no lysine [K]) kinases are serine-threonine protein kinases with an atypical placement of the catalytic lysine. Intronic deletions increase the expression of WNK1 in humans and cause pseudohypoaldosteronism type II, a form of hypertension. WNKs have been linked to ion carriers, but the underlying regulatory mechanisms are unknown. Here, we report a mechanism for the control of ion permeability by WNK1. We show that WNK1 activates the serum- and glucocorticoid-inducible protein kinase SGK1, leading to activation of the epithelial sodium channel. Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2. This finding provides compelling evidence that this molecular mechanism contributes to the pathogenesis of hypertension in pseudohypoaldosteronism type II caused by WNK1 and, possibly, in other forms of hypertension.
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PMID:WNK1 activates SGK1 to regulate the epithelial sodium channel. 1600 11

Sasang constitutional medicine is a major branch of Korean traditional Oriental medicine. The differences of disease susceptibility to be shown in Sasang constitution may be due to genetic factors. Therefore, the authors examined relationship between candidate genes of cerebral infarction (CI) and Sasang constitution. The homozygous deletion allele of the angiotensin converting enzyme gene (ACE/DD), homozygous threonine allele of the angiotensinogen gene (AGN/TT), and the e4 allele of the apolipoprotein E gene (ApoE/e4) are reported to be associated with ischemic heart disease. CI is another atherosclerotic disease; and the effects of these polymorphisms on CI have been confusing. This study investigated whether ACE/DD, AGN/TT, and ApoE/e4 genotypes are associated with CI and whether genetic risk is enhanced by Sasang constitutional classification. The authors ascertained these genotypes in patients with CI (N=211), diagnosed by brain computed tomography. Control subjects for the infarction group were randomly selected from 319 subjects matched for age, sex, and history of hypertension with patients. The ACE/DD genotype was not associated with CI. However, there was significant association between ApoE polymorphism and CI (chi2=15.089, p<.05). Furthermore, frequency of AGN/TT genotype was higher in the patients with CI than in the controls (chi2=20.072, p<.05). The frequency of T allele was 0.91 in patients and 0.82 in controls (chi2=17.237, p<.05). However, Sasang constitutional classification did not increase the relative risk for CI in the subjects with ApoE/e4 or AGN/T allele. These results suggest that ApoE and AGN polymorphism predict CI, but Sasang constitutional classification does not enhance the risk for CI associated with ApoE/e4 or AGN/TT in a Korean population.
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PMID:Candidate genes of cerebral infarction and traditional classification in Koreans with cerebral infarction. 1601 71

Two members of a recently discovered family of protein kinases {WNK1 and WNK4 [with no K (lysine) kinases-1 and -4]} are the cause of an inherited disease known as pseudohypoaldosteronism type II that features arterial hypertension. The family is known as WNK due to a lack of the invariant catalytic lysine in kinase subdomain II. The mechanisms by which WNKs regulate blood pressure are beginning to be understood at the physiological level from recent studies showing effects of WNK4 on several plasma membrane co-transporters and ion channels. However, little is known about the function of WNKs at the biochemical level. In this issue of the Biochemical Journal, Vitari et al. have shown that WNK1 and WNK4 interact with other kinases, SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress response kinase-1), which are involved in the regulation of ion transporters. WNK1 and WNK4 phosphorylate SPAK and OSR1, which in turn phosphorylate the N-terminal domain of the basolateral Na+-K+-2Cl- co-transporter, NKCCl. The phosphorylation site involved in SPAK or OSR1 activation is identified as a threonine residue within the T-loop.
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PMID:WNK lies upstream of kinases involved in regulation of ion transporters. 1617 16

Accumulating evidence strongly implicates the critical roles of intracellular signaling of angiotensin II (AngII) in mediating cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after vascular injury. The importance of AngII signals has also been reported in endothelial dysfunction and insulin resistance, two strong predictors of cardiovascular disease. Through its G protein-coupled AngII type-1 receptor (AT1), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases and serine/threonine kinases. Activation of these kinases requires both G protein-dependent and independent pathways, reactive oxygen species and a metalloprotease, and each kinase could be involved specifically in mediating pathophysiological function of the AT1 receptor target organs. In fact, some of the kinases are indispensable for AngII-induced hypertrophy and migration. The role of these AT1-activated kinases in mediating vascular remodeling, vascular contractility, endothelial dysfunction, and insulin resistance will be discussed in this review. In addition, the AT1 receptor undergoes rapid phosphorylation, desensitization, and internalization upon AngII stimulation. Recent studies with site-directed mutagenesis of the AT1 receptor not only elucidated a G protein interaction and desensitization of the receptor, but also demonstrated a structural requirement of the receptor for downstream signal transduction. Thus, AT1 mutants have provided an excellent means to examine the mechanism of signal transduction and their significance in mediating AngII function. Taken together, in this review, we will focus our discussion on the recent findings of the signal transduction research elucidating novel signaling mechanisms of the AT1 receptor that are relevant to the vascular pathophysiology of AngII.
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PMID:Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement. 1625 Aug 62

WNK1 and WNK4 [WNK, with no lysine (K)] are serine-threonine kinases that function as molecular switches, eliciting coordinated effects on diverse ion transport pathways to maintain homeostasis during physiological perturbation. Gain-of-function mutations in either of these genes cause an inherited syndrome featuring hypertension and hyperkalemia due to increased renal NaCl reabsorption and decreased K(+) secretion. Here, we reveal unique biochemical and functional properties of WNK3, a related member of the WNK kinase family. Unlike WNK1 and WNK4, WNK3 is expressed throughout the nephron, predominantly at intercellular junctions. Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively. In contrast to WNK4's inhibitory activity, kinase-active WNK3 is a potent activator of both NKCC2 and NCC-mediated transport. Conversely, in its kinase-inactive state, WNK3 is a potent inhibitor of NKCC2 and NCC activity. WNK3 regulates the activity of these transporters by altering their expression at the plasma membrane. Wild-type WNK3 increases and kinase-inactive WNK3 decreases NKCC2 phosphorylation at Thr-184 and Thr-189, sites required for the vasopressin-mediated plasmalemmal translocation and activation of NKCC2 in vivo. The effects of WNK3 on these transporters and their coexpression in renal epithelia implicate WNK3 in NaCl, water, and blood pressure homeostasis, perhaps via signaling downstream of vasopressin.
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PMID:WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. 1627 13

We examined the interactions between lifestyle and polymorphisms of salt-sensitive genes and their effects on hypertension in a general Japanese sample (The Shigaraki Study). The study group consisted of 2,902 subjects who underwent a medical examination in 1999 in Shigaraki, a suburban area in Shiga. Among 1,647 subjects not receiving antihypertensive medication, in a combined analysis of angiotensinogen (AGT) and adducin (ADD1) polymorphisms, double homozygosity of 235Thr or 460Trp was not found to be associated with hypertension. A multiple logistic regression analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [95% CI]: 1.06-1.08), body mass index (BMI) (OR: 1.18, 95% CI: 1.13-1.23), alcohol consumption (OR: 1.39, 95% CI: 1.16-1.66), family history of hypertension (OR: 1.57, 95% CI: 1.18-2.07), and combined AGT M235T Thr/Thr and ADD1 Trp/Trp polymorphisms (OR: 1.37, 95% CI: 1.03-1.82) were associated with hypertension. However, there was no interaction between eating salty food and combined AGT and ADD1 polymorphisms. Furthermore, eating salty food was not associated with hypertension in a multivariate analysis. Therefore, a combination of the AGT and ADD1 polymorphisms appears to be associated with hypertension. However, a simple questionnaire regarding salt intake was not sufficient to confirm the relationship between salt intake and hypertension and/or salt-sensitive genes.
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PMID:Combined analysis of polymorphisms in angiotensinogen and adducin genes and their effects on hypertension in a Japanese sample: The Shigaraki Study. 1639 68

WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia. Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis. Inhibition of ROMK by long WNK1 was synergistic with, but not dependent on, WNK4. A smaller transcript of WNK1 lacking the N-terminal 1-437 amino acids is expressed highly in the kidney. Whether expression of the KS-WNK1 (kidney-specific, KS) is altered in PHA II is not known. We found that KS-WNK1 did not inhibit ROMK1 but reversed the inhibition of ROMK1 caused by long WNK1. Consistent with the lack of inhibition by KS-WNK1, we found that amino acids 1-491 of the long WNK1 were sufficient for inhibiting ROMK. Dietary K(+) restriction decreases ROMK abundance in the renal cortical-collecting ducts by stimulating endocytosis, an adaptative response important for conservation of K(+) during K(+) deficiency. We found that K(+) restriction in rats increased whole-kidney transcript of long WNK1 while decreasing that of KS-WNK1. Thus, KS-WNK1 is a physiological antagonist of long WNK1. Hyperkalemia in PHA II patients with PHA II mutations may be caused, at least partially, by increased expression of long WNK1 with or without decreased expression of KS-WNK1.
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PMID:Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. 1642 87


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