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The B1-subunit of the H(+) ATPase is required for maximal urinary acidification.

Abstract
The multisubunit vacuolar-type H(+)ATPases mediate acidification of various intracellular organelles and in some tissues mediate H(+) secretion across the plasma membrane. Mutations in the B1-subunit of the apical H(+)ATPase that secretes protons in the distal nephron cause distal renal tubular acidosis in humans, a condition characterized by metabolic acidosis with an inappropriately alkaline urine. To examine the detailed cellular and organismal physiology resulting from this mutation, we have generated mice deficient in the B1-subunit (Atp6v1b1(-/-) mice). Urine pH is more alkaline and metabolic acidosis is more severe in Atp6v1b1(-/-) mice after oral acid challenge, demonstrating a failure of normal urinary acidification. In Atp6v1b1(-/-) mice, the normal urinary acidification induced by a lumen-negative potential in response to furosemide infusion is abolished. After an acute intracellular acidification, Na(+)-independent pH recovery rates of individual Atp6v1b1(-/-) intercalated cells of the cortical collecting duct are markedly reduced and show no further decrease after treatment with the selective H(+)ATPase inhibitor concanamycin. Apical expression of the alternative B-subunit isoform, B2, is increased in Atp6v1b1(-/-) medulla and colocalizes with the H(+)ATPase E-subunit; however, the greater severity of metabolic acidosis in Atp6v1b1(-/-) mice after oral acid challenge indicates that the B2-subunit cannot fully functionally compensate for the loss of B1. Our results indicate that the B1 isoform is the major B-subunit isoform that incorporates into functional, plasma membrane H(+)ATPases in intercalated cells of the cortical collecting duct and is required for maximal urinary acidification.
AuthorsKarin E Finberg, Carsten A Wagner, Matthew A Bailey, Teodor G Paunescu, Sylvie Breton, Dennis Brown, Gerhard Giebisch, John P Geibel, Richard P Lifton
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 38 Pg. 13616-21 (Sep 20 2005) ISSN: 0027-8424 [Print] United States
PMID16174750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Acids
  • Protein Subunits
  • Protons
  • Atp6v1b1 protein, mouse
  • Vacuolar Proton-Translocating ATPases
Topics
  • Acidosis, Renal Tubular (enzymology, genetics, urine)
  • Acids (administration & dosage, urine)
  • Animals
  • Cell Membrane (enzymology)
  • Humans
  • Hydrogen-Ion Concentration
  • Kidney Medulla (enzymology)
  • Kidney Tubules, Collecting (enzymology)
  • Mice
  • Mice, Knockout
  • Protein Subunits (genetics, metabolism)
  • Protons
  • Vacuolar Proton-Translocating ATPases (deficiency, metabolism)

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