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 Na+/H+ exchangers (NHEs) are membrane-bound transporters that catalyze the electro-neutral movement of extracellular Na+ for intracellular H+. NHE genes play a critical role in pH homeostasis and cellular volume regulation and can be considered candidate genes for essential hypertension and renal disease. This study was performed to determine whether the NHE genes contributed to genetic susceptibility in end-stage renal disease (ESRD). To date, 5 isoforms of NHE have been cloned in mammals (NHE1 to NHE5). The complementary DNA (cDNA) sequences of NHE1 to NHE3 and NHE5 are known in humans. Because the chromosomal structure of the NHE genes is unknown, we used cDNA sequences to design polymerase chain reaction primers for use in radiation hybrid mapping. Radiation hybrid mapping of NHE genes identified nearby polymorphic markers for NHE1 to NHE3 (NHE1: D1S197, D1S2677; NHE2: D2S373, D2S1789; and NHE3: D5S678, D5S2005). We used these markers, and other previously identified polymorphic markers for NHE5, in linkage and association analyses of ESRD. The NHE1 to NHE3 and NHE5 loci did not demonstrate evidence for linkage to ESRD. However, NHE5 showed significant evidence for association (P</=1.0x10(-4)). The strongest evidence for association was observed with allele 6 of NHE5 (P</=0.001 to 0. 01). Allele 6 appeared to have a renoprotective effect, with a frequency of 0.15 in the control population and 0.06 to 0.09 in patients with ESRD. The combined approach of designing primers from cDNA and radiation hybrid mapping has proven successful in identifying polymorphisms for human genes of which only cDNA sequences were previously available. The NHE primers and associated polymorphic loci identified in this study can be used in genomic, linkage, and association analysis of NHE genes in future genetic studies of hypertension and renal failure. Given the allelic association, further evaluation of the role of NHE5 in ESRD susceptibility appears warranted.
Hypertension 2000 Jan
PMID:Human Na+/H+ exchanger genes : identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease. 1064 88

Na+/H+ exchangers (NHEs) extrude protons from, and take up sodium ions into cells. Six isoforms, NHE-1 - NHE-6, have been cloned. NHE proteins are composed of an N-terminal domain, which most likely crosses the cell membrane 12 times and constitutes the cation exchange machinery, and a C-terminal tail, which modulates the exchanger by interacting with protein kinases and regulatory factors. The "house-keeping" NHE-1 is located at the basolateral membrane of most renal tubule cells; NHE-2 is located apically in selected nephron segments. As suggested from data with NHE-1 and NHE-2 deficient mice, both isoforms play a minor role in renal salt and water handling. NHE-3 is located at the apical membrane of proximal tubule and thick ascending limb cells, is involved in Na+ absorption, and is responsible for the majority of bicarbonate absorption. NHE-3 is modulated by the NHE regulating factor, which interacts with further proteins, protein kinases, and the cytoskeleton. Downregulation of NHE-3 by parathyroid hormone, dopamine, and by an increase in blood pressure leads to saluresis/diuresis. The failure of dopamine to downregulate NHE-3 may cause hypertension through renal salt and water retention. NHE-3 knockouts are hypotonic and can not survive on low salt diet. In chronic acidosis, NHE-3 is upregulated possibly through increased local endothelin production. NHE4 has been found mostly in renal medulla. The precise function of this isoform, which is activated by hypertonicity and can perform K+/H+ exchange, is not clear. The segmental location and function of NHE-5 and NHE-6 in the kidney are unknown at present.
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PMID:The Na+/H+ exchanger gene family. 1202 19