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)

An age- and blood pressure-associated increase in methylglyoxal (MG) and MG-induced advanced glycation endproducts (AGEs), including N(epsilon)-carboxyethyl-lysine (CEL) and N(epsilon)-carboxymethyl-lysine (CML), in the kidney of spontaneously hypertensive rats (SHR) has been shown. In the present study, gender-related changes in AGEs and nitric oxide synthase were investigated in Sprague-Dawley (SD) and stroke-prone SHR (SHRsp) rats. Immunohistochemical analyses were conducted on kidneys from 24-week-old male and female SD rats as well as SHRsp. The systolic blood pressure of SHRsp was significantly higher than that of SD rats. Male SD rats had more intense kidney staining for CEL than female SD rats. Both male and female SHRsp had more marked CEL and CML staining localized to kidney tubules, as opposed to SD rats. Female rats showed more staining in glomerular vessels than male rats in both SD and SHRsp. Nuclei containing nuclear factor-kappaB (NF-kappaB) p65 and activated macrophages were seen in the kidney from SHRsp, not so much in SD rats, localized to renal tubules in male and glomerular vessels in female SHRsp. A higher protein level of NF-kappaB p65 was found in SHRsp than in SD rats. SD rats had more intense kidney neuronal nitric oxide synthase staining than SHRsp. The intensity of inducible nitric oxide synthase staining was significantly higher in SHRsp than in SD rats, with no gender differences in either strain. SHRsp and male rats exhibited higher AGEs and oxidative stress than SD and female rats, respectively. These differences might partly account for the development of hypertension in SHRsp and the higher vulnerability of male animals to renal pathology.
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PMID:Gender-related differences in advanced glycation endproducts, oxidative stress markers and nitric oxide synthases in rats. 1640 17

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

Improving models of human stroke by the use of aged animals has been advocated; however the commonly used rat middle cerebral artery thread-occlusion model has produced suboptimal stroke induction and excess mortality in aged rats. We report the development of a modified method for silicone-coating the tip of occluding threads which produces a malleable silicone-coated tip which is firmly bonded and of highly consistent diameter, and overcomes problems of thread insertion through the narrowed carotid canal found in aged animals. Comparison of stroke outcomes and mortality were made between these threads and heat-treated poly-L-lysine coated threads. The rate of successful stroke induction in aged rats was significantly improved (from 14% to 86%). Similarly, mortality fell from 21-31% to 3-7% or less in both young and old rats with or without diabetes and hypertension. An occluding thread tip diameter of 0.35-0.38 mm was optimal for induction of mid-sized strokes in both young and old rats. This method of thread manufacture overcomes problems of inconsistency of diameter and bonding of the silicone-coated tip, and these threads produce significant improvements in stroke induction by MCA occlusion, particularly in aged animals and those with co-morbidities.
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PMID:Modification of the method of thread manufacture improves stroke induction rate and reduces mortality after thread-occlusion of the middle cerebral artery in young or aged rats. 1651 79

The SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase-1) kinases interact and phosphorylate NKCC1 (Na+-K+-2Cl- co-transporter-1), leading to its activation. Recent studies indicated that SPAK and OSR1 are phosphorylated and activated by the WNK1 [with no K (lysine) protein kinase-1] and WNK4, genes mutated in humans affected by Gordon's hypertension syndrome. In the present study, we have identified three residues in NKCC1 (Thr175/Thr179/Thr184 in shark or Thr203/Thr207/Thr212 in human) that are phosphorylated by SPAK and OSR1, and have developed a peptide substrate, CATCHtide (cation chloride co-transporter peptide substrate), to assess SPAK and OSR1 activity. Exposure of HEK-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of NKCC1, increased phosphorylation of NKCC1 at the sites targeted by SPAK/OSR1. The residues on NKCC1, phosphorylated by SPAK/OSR1, are conserved in other cation co-transporters, such as the Na+-Cl- co-transporter, the target of thiazide drugs that lower blood pressure in humans with Gordon's syndrome. Furthermore, we characterize the properties of a 92-residue CCT (conserved C-terminal) domain on SPAK and OSR1 that interacts with an RFXV (Arg-Phe-Xaa-Val) motif present in the substrate NKCC1 and its activators WNK1/WNK4. A peptide containing the RFXV motif interacts with nanomolar affinity with the CCT domains of SPAK/OSR1 and can be utilized to affinity-purify SPAK and OSR1 from cell extracts. Mutation of the arginine, phenylalanine or valine residue within this peptide abolishes binding to SPAK/OSR1. We have identified specific residues within the CCT domain that are required for interaction with the RFXV motif and have demonstrated that mutation of these in OSR1 inhibited phosphorylation of NKCC1, but not of CATCHtide which does not possess an RFXV motif. We establish that an intact CCT domain is required for WNK1 to efficiently phosphorylate and activate OSR1. These data establish that the CCT domain functions as a multipurpose docking site, enabling SPAK/OSR1 to interact with substrates (NKCC1) and activators (WNK1/WNK4).
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PMID:Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. 1666 87

Dihydropyridines (DHPs) are an important class of drugs, used extensively in the treatment of angina pectoris, hypertension, and arrhythmia. The molecular mechanism by which DHPs modulate Ca(2+) channel function is not known in detail. We have found that DHP binding is allosterically coupled to Ca(2+) binding to the selectivity filter of the skeletal muscle Ca(2+) channel Ca(V)1.1, which initiates excitation-contraction coupling and conducts L-type Ca(2+) currents. Increasing Ca(2+) concentrations from approximately 10 nM to 1 mM causes the DHP receptor site to shift from a low-affinity state to a high-affinity state with an EC(50) for Ca(2+) of 300 nM. Substituting each of the four negatively charged glutamate residues that form the ion selectivity filter with neutral glutamine or positively charged lysine residues results in mutant channels whose DHP binding affinities are decreased up to 10-fold and are up to 150-fold less sensitive to Ca(2+) than wild-type channels. Analysis of mutations of amino acid residues adjacent to the selectivity filter led to identification of Phe-1013 and Tyr-1021, whose mutation causes substantial changes in DHP binding. Thermo-dynamic mutant cycle analysis of these mutants demonstrates that Phe-1013 and Tyr-1021 are energetically coupled when a single Ca(2+) ion is bound to the channel pore. We propose that DHP binding stabilizes a nonconducting state containing a single Ca(2+) ion in the pore through which Phe-1013 and Tyr-1021 are energetically coupled. The selectivity filter in this energetically coupled high-affinity state is blocked by bound Ca(2+), which is responsible for the high-affinity inhibition of Ca(2+) channels by DHP antagonists.
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PMID:Allosteric interactions required for high-affinity binding of dihydropyridine antagonists to Ca(V)1.1 Channels are modulated by calcium in the pore. 1667 61

Gordon's syndrome, also known as pseudohypoaldosteronism type II (PHA II) or familial hypertension with hyperkalemia, is an autosomal-dominant disease characterized by hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. Recent positional cloning has linked mutations of WNK1 and WNK4 to Gordon's syndrome. With-no-lysine [K] (WNK) kinases are a new family of large serine-threonine protein kinases with an atypical placement of the catalytic lysine. Here, we review the pathogenesis of PHA II based on current understanding of the actions of WNK1 and WNK4 on Na+ and K+ handling in the renal distal tubule.
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PMID:Role of with-no-lysine [K] kinases in the pathogenesis of Gordon's syndrome. 1668 63

The WNK (with no lysine kinase) kinases are a novel class of serine/threonine kinases that lack a characteristic lysine residue for ATP docking. Both WNK1 and WNK4 are expressed in the mammalian kidney, and mutations in either can cause the rare familial syndrome of hypertension and hyperkalemia (Gordon syndrome, or pseudohypoaldosteronism type 2). The molecular basis for the action of WNK4 is through alteration in the membrane expression of the NaCl co-transporter (NCCT) and the renal outer-medullary K channel KCNJ1 (ROMK). The actions of WNK1 are less well defined, and evidence to date suggests that it can affect NCCT expression but only in the presence of WNK4. The results of co-expressing WNK1 with ROMK in Xenopus oocytes are reported for the first time. These studies show that WNK1 is able to suppress total current directly through ROMK by causing a marked reduction in its surface expression. The effect is mimicked by a kinase-dead mutant of WNK1 (368D > A), suggesting that it is not dependent on its catalytic activity. Study of the time course of ROMK expression further suggests that WNK1 accelerates trafficking of ROMK from the membrane, and this effect seems to be dynamin dependent. Using fragments of full-length WNK1, it also is shown that the effect depends on residues in the middle section of the protein (502 to 1100 WNK1) that contains the acidic motif. Together, these findings emphasize that the molecular mechanisms that underpin WNK1 regulation of ROMK expression are distinct from those that affect NCCT expression.
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PMID:WNK1 affects surface expression of the ROMK potassium channel independent of WNK4. 1677 35

The novel serine/threonine kinases (with no lysine kinases or WNKs), WNK1 and WNK4, are encoded by the disease genes for Gordon syndrome (PRKWNK1 and PRKWNK4), a rare monogenic syndrome of hypertension and hyperkalemia. These proteins alter the expression of the thiazide-sensitive Na/Cl cotransporter (NCCT) in Xenopus laevis oocytes, although the details are controversial. We describe here our own experience and confirm that kinase-dead WNK4 (318D>A) is unable to affect Na+ fluxes through the thiazide-sensitive Na/Cl transporter (NCCT) or its membrane expression as an ECFP-NCCT fusion protein. However, the kinase domain is not sufficient for a functional WNK4 since deletion of the acidic motif (a motif unique to WNK family members) completely abolishes functional activity. Indeed, the NH2 terminal of WNK4 (1-620) containing the kinase domain and acidic motif retains full activity, but does not interact directly with NCCT in pull-down assays. Coexpression of WNK1 antagonizes the action of WNK4, and kinase-dead WNK1 (368D>A) or WNK1 carrying a WNK4 disease mutation (565Q>E) behaves in the same way as wild-type WNK1. This suggests kinase activity and charge conservation within the acidic motif are not essential for the WNK1-WNK4 interaction. We also report that WNK4 probably reduces surface expression largely through an effect on forward trafficking. Hence, the effect of WNK4 on NCCT expression is mimicked by dynamin, but the dominant-negative K44A dynamin mutant does not block the action of WNK4 itself. These results further highlight important differences in the mechanism by which WNK kinases affect expression of NCCT vs. other membrane proteins such as ROMK.
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PMID:Regulation of the expression of the Na/Cl cotransporter by WNK4 and WNK1: evidence that accelerated dynamin-dependent endocytosis is not involved. 1678 37

WNK1 and WNK4 are unusual serine/threonine kinases with atypical positioning of the catalytic active-site lysine (WNK: With-No-K[lysine]). Mutations in these WNK kinase genes can cause familial hyperkalemic hypertension (FHHt), an autosomal dominant, hypertensive, hyperkalemic disorder, implicating this novel WNK pathway in normal regulation of BP and electrolyte balance. Full-length (WNK1-L) and short (WNK1-S) kinase-deficient WNK1 isoforms previously have been identified. Importantly, WNK1-S is overwhelmingly predominant in kidney. Recent Xenopus oocyte studies implicate WNK4 in inhibition of both thiazide-sensitive co-transporter-mediated Na+ reabsorption and K+ secretion via renal outer medullary K+ channel and now suggest that WNK4 is inhibited by WNK1-L, itself inhibited by WNK1-S. This study examined WNK pathway gene expression in mouse kidney and its regulation in vivo. Expression of WNK1-S and WNK4 is strongest in distal tubule, dropping sharply in collecting duct and with WNK4 also expressed in thick ascending limb and the macula densa. These nephron segments that express WNK1-S and WNK4 mRNA have major influence on long-term NaCl reabsorption, BP, K+, and acid-base balance, processes that all are disrupted in FHHt. In vivo, this novel WNK pathway responds with significant upregulation of WNK1-S and WNK4 with high K+ intake and reduction in WNK1-S on chronic lowering of K+ or Na+ intake. A two-compartment distal nephron model explains these in vivo findings and the pathophysiology of FHHt well, with WNK and classic aldosterone pathways responding to drivers from K+ balance, extracellular volume, and aldosterone and cross-talk through distal Na+ delivery regulating electrolyte balance and BP.
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PMID:Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. 1689 20

All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.
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PMID:Roles of transglutaminases in cardiac and vascular diseases. 1712 61


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