| Targeted mutation of SLC4A5 induces arterial hypertension and renal metabolic acidosis. | |
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MedLine Citation:
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PMID: 22082831 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The human SLC4A5 gene has been identified as a hypertension susceptibility gene based on the association of single nucleotide polymorphisms with blood pressure levels and hypertension status. The biochemical basis of this association is unknown particularly since no single gene variant was linked to hypertension in humans. SLC4A5 (NBCe2, NBC4) is expressed in the collecting duct of the kidney and acts as an electrogenic ion-transporter that transports sodium and bicarbonate with a 1:2 or 1:3 stoichiometry allowing bicarbonate reabsorption with relatively minor concurrent sodium uptake. We have mutated the Slc4a5 gene in mice, which caused a persistent increase in systolic and diastolic blood pressure. Slc4a5 mutant mice also displayed a compensated metabolic acidosis and hyporeninemic hypoaldosteronism. Analysis of kidney physiology revealed elevated fluid intake and urine excretion and increased glomerular filtration rate. Transcriptome analysis uncovers possible compensatory mechanisms induced by SLC4A5 mutation including upregulation of SLC4A7 and pendrin as well as molecular mechanisms associated with hypertension. Induction of metabolic alkalosis eliminated the blood pressure difference between WT and Slc4a5 mutant mice. We conclude that impairment of the function of SLC4A5 favors development of a hypertensive state. We reason that loss of sodium-sparing bicarbonate reabsorption by SLC4A5 initiates a regulatory cascade consisting of compensatory bicarbonate reabsorption via other sodium-bicarbonate transporters (e.g. SLC4A7) at the expense of an increased sodium uptake. This will ultimately raise blood pressure and cause hypoaldosteronism, thus providing a mechanistic explanation for the linkage of the SLC4A5 locus to hypertension in humans. |
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Authors:
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Nicole Gröger; Helga Vitzthum; Henning Fröhlich; Marcus Krüger; Heimo Ehmke; Thomas Braun; Thomas Boettger |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-14 |
Journal Detail:
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Title: Human molecular genetics Volume: - ISSN: 1460-2083 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9208958 Medline TA: Hum Mol Genet Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, D-61231 Bad Nauheim, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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