title: Targeted mutation of SLC4A5 induces arterial hypertension and renal metabolic acidosis.
abstract: The human SLC4A5 gene has been identified as a hypertension susceptibility gene based on the association of single nucleotide polymorphisms with blood pressure (BP) 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 BP. 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 BP difference between wild-type and Slc4a5 mutant mice. We conclude that the impairment of the function of SLC4A5 favors development of a hypertensive state. We reason that the 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 BP and cause hypoaldosteronism, thus providing a mechanistic explanation for the linkage of the SLC4A5 locus to hypertension in humans.
authors.affiliation: Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, D-61231 Bad Nauheim, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gröger
authors.forename: Helga
authors.initials: H
authors.lastname: Vitzthum
authors.forename: Henning
authors.initials: H
authors.lastname: Fröhlich
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
mesh_terms: D000136:Acid-Base Equilibrium; D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001769:Blood; D001774:Blood Chemical Analysis; D001794:Blood Pressure; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D017384:Sequence Deletion; D012964:Sodium / Q000378:metabolism; D017693:Sodium Bicarbonate / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics* / Q000378:metabolism*; D014554:Urination; D014556:Urine / Q000737:chemistry
chemical_list: C530862:SLC4A5 protein, mouse; C498904:Slc4a7 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D017693:Sodium Bicarbonate; D012964:Sodium