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The B1 H + -ATPase ( Atp6v1b1 ) Subunit in Non-Type-A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defence Against Alkalosis


Bourgeois, Soline; Kovacikova, Jana; Bugarski, Milica; Bettoni, Carla; Gehring, Nicole; Hall, Andrew; Wagner, Carsten A (2024). The B1 H + -ATPase ( Atp6v1b1 ) Subunit in Non-Type-A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defence Against Alkalosis. Journal of the American Society of Nephrology (JASN), 35(1):7-21.

Abstract

BACKGROUND: Non-type-A intercalated cells (IC) in the collecting duct system express the luminal Cl - /HCO 3- exchanger pendrin and apical and/or basolateral H + -ATPases containing the B1 subunit isoform. Non-type-A ICs excrete bicarbonate during metabolic alkalosis. Mutations in the B1 subunit (ATP6V1B1) cause distal renal tubular acidosis due to its role in acid secretory type-A ICs. The function of B1 in non-type-A ICs has remained elusive.
METHODS: We examined responses of Atp6v1b1-/- and Atp6v1b1+/+ mice to an alkali load and to chronic treatment with furosemide.
RESULTS: An alkali load or one week of furosemide resulted in a more pronounced hypokalemic alkalosis in male ATP6v1b1-/- versus Atp6v1b1+/+ mice that could not be compensated by respiration. Total pendrin expression and activity in non-type-A IC of ex vivo microperfused cortical collecting ducts (CCDs) were reduced, and β2-adrenergic stimulation of pendrin activity was blunted in ATP6v1b1-/- mice. Basolateral H + -ATPase activity was strongly reduced, even though basolateral expression of the B2 isoform was increased. Ligation assays for H + -ATPase subunits indicated impaired assembly of V 0 and V 1 H + -ATPase domains. During chronic furosemide treatment, ATP6v1b1-/- mice also showed polyuria and hyperchloruria versus Atp6v1b1+/+ . Expression of pendrin, the water channel AQP2, and subunits of the epithelial sodium channel ENaC were reduced.
CONCLUSION: Our data demonstrate a critical role of H + -ATPases in non-type-A IC function protecting against alkalosis and reveal a hitherto unrecognized need of basolateral B1 isoform for a proper H + -ATPase complexes assembly and ability to be stimulated.

Abstract

BACKGROUND: Non-type-A intercalated cells (IC) in the collecting duct system express the luminal Cl - /HCO 3- exchanger pendrin and apical and/or basolateral H + -ATPases containing the B1 subunit isoform. Non-type-A ICs excrete bicarbonate during metabolic alkalosis. Mutations in the B1 subunit (ATP6V1B1) cause distal renal tubular acidosis due to its role in acid secretory type-A ICs. The function of B1 in non-type-A ICs has remained elusive.
METHODS: We examined responses of Atp6v1b1-/- and Atp6v1b1+/+ mice to an alkali load and to chronic treatment with furosemide.
RESULTS: An alkali load or one week of furosemide resulted in a more pronounced hypokalemic alkalosis in male ATP6v1b1-/- versus Atp6v1b1+/+ mice that could not be compensated by respiration. Total pendrin expression and activity in non-type-A IC of ex vivo microperfused cortical collecting ducts (CCDs) were reduced, and β2-adrenergic stimulation of pendrin activity was blunted in ATP6v1b1-/- mice. Basolateral H + -ATPase activity was strongly reduced, even though basolateral expression of the B2 isoform was increased. Ligation assays for H + -ATPase subunits indicated impaired assembly of V 0 and V 1 H + -ATPase domains. During chronic furosemide treatment, ATP6v1b1-/- mice also showed polyuria and hyperchloruria versus Atp6v1b1+/+ . Expression of pendrin, the water channel AQP2, and subunits of the epithelial sodium channel ENaC were reduced.
CONCLUSION: Our data demonstrate a critical role of H + -ATPases in non-type-A IC function protecting against alkalosis and reveal a hitherto unrecognized need of basolateral B1 isoform for a proper H + -ATPase complexes assembly and ability to be stimulated.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Language:English
Date:1 January 2024
Deposited On:20 Dec 2023 12:41
Last Modified:30 Apr 2024 01:44
Publisher:American Society of Nephrology
ISSN:1046-6673
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1681/ASN.0000000000000259
PubMed ID:37990364
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