title: Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl-/HCO3- exchanger (slc4a1).
abstract: Mutations in the human gene that encodes the AE1 Cl(-)/HCO(3)(-) exchanger (SLC4A1) cause autosomal recessive and dominant forms of distal renal tubular acidosis (dRTA). A mouse model that lacks AE1/slc4a1 (slc4a1-/-) exhibited dRTA characterized by spontaneous hyperchloremic metabolic acidosis with low net acid excretion and, inappropriately, alkaline urine without bicarbonaturia. Basolateral Cl(-)/HCO(3)(-) exchange activity in acid-secretory intercalated cells of isolated superfused slc4a1-/- medullary collecting duct was reduced, but alternate bicarbonate transport pathways were upregulated. Homozygous mice had nephrocalcinosis associated with hypercalciuria, hyperphosphaturia, and hypocitraturia. A severe urinary concentration defect in slc4a1-/- mice was accompanied by dysregulated expression and localization of the aquaporin-2 water channel. Mice that were heterozygous for the AE1-deficient allele had no apparent defect. Thus, the slc4a1-/- mouse is the first genetic model of complete dRTA and demonstrates that the AE1/slc4a1 Cl(-)/HCO(3)(-) exchanger is required for maintenance of normal acid-base homeostasis by distal renal regeneration of bicarbonate in the mouse as well as in humans.
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stehberger
authors.forename: Boris E
authors.initials: BE
authors.lastname: Shmukler
authors.forename: Alan K
authors.initials: AK
authors.lastname: Stuart-Tilley
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D000137:Acid-Base Imbalance / Q000097:blood / Q000652:urine; D000141:Acidosis, Renal Tubular / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000652:urine; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics* / Q000378:metabolism; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009397:Nephrocalcinosis / Q000209:etiology / Q000473:pathology
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D017920:Antiporters