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)

With-No-Lysine [K] (WNKs) are a recently discovered family of serine/threonine protein kinases that contain a uniquely structured catalytic domain. Mutations in the genes encoding two family members, WNK1 and WNK4, cause a chloride-dependent, thiazide-sensitive inherited syndrome of hypertension and hyperkalemia. Over the past 5 years, physiologic studies have demonstrated that these proteins regulate transcellular and paracellular epithelial ion flux. In this mini review, we discuss WNK1 and WNK4 gene products and their regulatory effects on sodium chloride and potassium handling in the aldosterone-sensitive distal nephron. Experimental observations regarding the effects of these proteins on transport processes mediated by the thiazide-sensitive Na-Cl co-transporter, the epithelial sodium channel, the renal outer medullary potassium channel, and the paracellular pathway integrate into a model that suggests an essential role for WNKs in coordinating renal Na-Cl reabsorption and K(+) secretion.
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PMID:WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. 1682 Jul 87

Gitelman's syndrome (GS) is a variant of Bartter's syndrome (BS) characterized by hypokalemic alkalosis, hypomagnesemia, hypocalciuria and secondary aldosteronism without hypertension. A 31-year-old Japanese man who had suffered from mild hypokalemia for 10 years was admitted to our hospital. He had metabolic alkalosis, hypokalemia and hypocalciuria. Since he had two missense mutations (R261C and L623P) in the thiazide-sensitive Na-Cl cotransporter (TSC) gene (SLC12A3), he was diagnosed as having GS. He showed hyperreninism and a high angiotensin I (Ang I) level, whereas his angiotensin II (Ang II) and aldosterone levels were not elevated. His angiotensin converting enzyme (ACE) activities were normal, and administration of captopril inhibited the production of Ang II and aldosterone. We evaluated the Ang II-forming activity (AIIFA) of other enzymes in his lymphocytes. Interestingly, chymase-dependent AIIFA was not detected in the lymphocytes. Together, these results suggest that the lack of chymase activity resulted in the manifestation of GS without hyperaldosteronism.
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PMID:A case of Gitelman's syndrome with decreased angiotensin II-forming activity. 1704 67

We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS.
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PMID:A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension. 1705 86

Inherited tubular disorders associated with metabolic alkalosis are caused by several gene mutations encoding different tubular transporters responsible for NaCl renal handling. Body volume and renin-angiotensin-aldosterone system status are determined by NaCl reabsorption in the distal nephron. Two common hallmarks in affected individuals: hypokalemia and normal / high blood pressure, support the differential diagnosis. Bartter's syndrome, characterized by hypokalemia and normal blood pressure, is a heterogenic disease caused by the loss of function of SLC12A1 (type 1), KCNJ1 (type 2), CLCNKB (type 3), or BSND genes (type 4). As a result, patients present with renal salt wasting and hypercalciuria. Gitelman's syndrome is caused by the loss of funcion of the SLC12A3 gene and may resemble Bartter's syndrome, though is associated with the very low urinary calcium. Liddle's syndrome, also with similar phenotype but with hypertension, is produced by the gain of function of the SNCC1B or SNCC1G genes, and must be distinguished from other entities of inherited hypertension such as Apparently Mineralocorticoid Excess, of glucocorticoid remediable hypertension.
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PMID:Inherited renal tubulopathies associated with metabolic alkalosis: effects on blood pressure. 1727 79

The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice.
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PMID:The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. 1797 63

The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)-causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.
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PMID:Rare independent mutations in renal salt handling genes contribute to blood pressure variation. 1844 83

Two members of a recently discovered family of protein kinases are the cause of an inherited disease known as pseudohypoaldosteronism type II (PHAII). These patients exhibit arterial hypertension together with hyperkalemia and metabolic acidosis. This is a mirror image of Gitelman disease that is due to inactivating mutations of the SLC12A3 gene that encodes the thiazide-sensitive Na(+):Cl(-) cotransporter. The uncovered genes causing PHAII encode for serine/threonine kinases known as WNK1 and WNK4. Physiological and biochemical studies have revealed that WNK1 and WNK4 modulate the activity of several transport pathways of the aldosterone-sensitive distal nephron, thus increasing our understanding of how diverse renal ion transport proteins are coordinated to regulate normal blood pressure levels. Observations discussed in the present work place WNK1 and WNK4 as genes involved in the genesis of essential hypertension and as potential targets for the development of antihypertensive drugs.
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PMID:WNK kinases, renal ion transport and hypertension. 1854 46

Thiazolidinediones increase tissue insulin sensitivity and are protective against worsening of nephropathy and hypertension in diabetes. Mechanisms underlying protection at the renal level likely involve a variety of unknown changes in gene expression. We examined kidney gene expression in obese and lean Zucker rats in response to rosiglitazone (Avandia), a peroxisome proliferator activated receptor (gamma-subtype) agonist. Lean and obese Zucker rats were treated with either control chow or chow with added rosiglitazone (3 mg/kg x bw) for 12 weeks (n = 3/group). Total kidney mRNA expression was evaluated using the Affymetrix Rat Genome 230 2.0 GeneChip. 903 probe sets were significantly (P < 0.05) altered with at least 1.5-fold changes between groups. In untreated obese rats, 300 probe sets were increased and 244 decreased, relative to lean. Increased genes included the beta-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter, and aquaporin 3. Decreased genes included angiotensin converting enzyme, type 1 (ACE1). FatiGO analysis showed that the highest number of altered genes between lean and obese belonged to the categories: ion binding, hydrolase activity, and protein binding. RGZ increased expression of uncoupling protein 1 (UCP1), CD36, and fatty acid binding protein 4 (FAbp4) in both lean and obese rats. In obese rats, 33 genes were normalized by RGZ (no longer different from lean) including ACE1, fatty acid synthase (Fasn), and stearoyl-coenzyme A desaturase (SCD1). Ingenuity Pathways System analysis of genes upregulated by RGZ in obese rats revealed two major nodes affected: PPAR-gamma and tumor necrosis factor alpha (TNF-alpha).
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PMID:Chronic rosiglitazone therapy normalizes expression of ACE1, SCD1 and other genes in the kidney of obese Zucker rats as determined by microarray analysis. 1870 Feb 76

Genome-wide association scans are beginning to identify risk alleles for a number of complex diseases and traits. Essential hypertension looked as though it would be an exception to this trend after the Wellcome Trust Case Control Consortium data were published in 2007. However, more recent scans and meta-analyses have reversed the fortunes of essential hypertension. A number of loci have been identified, including a new antihypertensive drug target in the guise of the serine/threonine kinase SPAK. This kinase forms part of a novel kinase cascade that regulates the NCCT (Na+/Cl- co-transporter; SLC12A3) in the kidney and is defective in a rare Mendelian hypertension syndrome (Gordon's syndrome). Genome-wide scans are also being used to look for alleles to predict individual response to antihypertensive drugs and their risk of causing side-effects. The results of these are expected in the near future and may finally deliver the long-awaited goal of personalized drug therapy for hypertensive patients.
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PMID:Dissecting complex traits: recent advances in hypertension genomics. 1943 27

Since the discovery of mutations in the WNK1 and WNK4 genes in pseudohypoaldosteronism type II (PHAII), the pathophysiological role of WNK kinases in hypertension and renal ion transport has been a hot topic for investigation. Analyses from a mouse model carrying the same mutation as seen in PHAII patients, reveal a new signal cascade in the kidney that regulates NaCl and K balance in the body. WNK kinases phosphorylate and activate oxidative stress responsive kinase 1 (OSR1) and STE20-like proline and alanine-rich kinase (SPAK), and OSR1 and SPAK phosphorylate and activate the thiazide-sensitive Na-Cl cotransporter (NCC). Furthermore, this cascade is regulated by aldosterone, indicating that WNK-OSR1/SPAK-NCC cooperates with this system including the epithelial Na channel (ENaC) to conserve NaCl. With regard to K excretion, however, both systems work in opposite directions whereby PHAII and Liddle syndrome show hyperkalemia and hypokalemia, respectively. Thus, the identification of such aldosterone effecters other than ENaC, will reveal a novel regulatory mechanism of K excretion in the distal nephron, and also provides basic evidence for the therapeutic use of thiazide in various clinical situations.
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PMID:Pathophysiological roles of WNK kinases in the kidney. 2049 May 38


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