Deletion of hensin/DMBT1 blocks conversion of β- To α-intercalated cells and induces distal renal tubular acidosis

Xiaobo Gao, Dominique Eladari, Francoise Leviel, Ben Yi Tew, Cristina Miró-Julià, Faisal Cheema, Lance Miller, Raoul Nelson, Teodor G. Pǎunescu, Mary McKee, Dennis Brown, Qais Al-Awqati

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Acid-base transport in the renal collecting tubule is mediated by two canonical cell types: the β-intercalated cell secretes HCO 3 by an apical Cl:HCO 3 named pendrin and a basolateral vacuolar (V)- ATPase. Acid secretion is mediated by the α-intercalated cell, which has an apical V-ATPase and a basolateral Cl:HCO 3 exchanger (kAE1). We previously suggested that the β-cell converts to the α-cell in response to acid feeding, a process that depended on the secretion and deposition of an extracellular matrix protein termed hensin (DMBT1). Here, we show that deletion of hensin from intercalated cells results in the absence of typical α-intercalated cells and the consequent development of complete distal renal tubular acidosis (dRTA). Essentially all of the intercalated cells in the cortex of the mutant mice are canonical β-type cells, with apical pendrin and basolateral or diffuse/bipolar V-ATPase. In the medulla, however, a previously undescribed cell type has been uncovered, which resembles the cortical β-intercalated cell in ultrastructure, but does not express pendrin. Polymerization and deposition of hensin (in response to acidosis) requires the activation of β1 integrin, and deletion of this gene from the intercalated cell caused a phenotype that was identical to the deletion of hensin itself, supporting its critical role in hensin function. Because previous studies suggested that the conversion of β- toα-intercalated cells is a manifestation of terminal differentiation, the present results demonstrate that this differentiation proceeds from HCO 3 secreting to acid secreting phenotypes, a process that requires deposition of hensin in the ECM.

Original languageEnglish (US)
Pages (from-to)21872-21877
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number50
DOIs
StatePublished - Dec 14 2010
Externally publishedYes

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Renal Tubular Acidosis
Acids
Adenosine Triphosphatases
Vacuolar Proton-Translocating ATPases
Phenotype
Extracellular Matrix Proteins
Gene Deletion
Acidosis
Integrins
Polymerization

ASJC Scopus subject areas

  • General

Cite this

Deletion of hensin/DMBT1 blocks conversion of β- To α-intercalated cells and induces distal renal tubular acidosis. / Gao, Xiaobo; Eladari, Dominique; Leviel, Francoise; Tew, Ben Yi; Miró-Julià, Cristina; Cheema, Faisal; Miller, Lance; Nelson, Raoul; Pǎunescu, Teodor G.; McKee, Mary; Brown, Dennis; Al-Awqati, Qais.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 50, 14.12.2010, p. 21872-21877.

Research output: Contribution to journalArticle

Gao, X, Eladari, D, Leviel, F, Tew, BY, Miró-Julià, C, Cheema, F, Miller, L, Nelson, R, Pǎunescu, TG, McKee, M, Brown, D & Al-Awqati, Q 2010, 'Deletion of hensin/DMBT1 blocks conversion of β- To α-intercalated cells and induces distal renal tubular acidosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21872-21877. https://doi.org/10.1073/pnas.1010364107
Gao, Xiaobo ; Eladari, Dominique ; Leviel, Francoise ; Tew, Ben Yi ; Miró-Julià, Cristina ; Cheema, Faisal ; Miller, Lance ; Nelson, Raoul ; Pǎunescu, Teodor G. ; McKee, Mary ; Brown, Dennis ; Al-Awqati, Qais. / Deletion of hensin/DMBT1 blocks conversion of β- To α-intercalated cells and induces distal renal tubular acidosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 50. pp. 21872-21877.
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T1 - Deletion of hensin/DMBT1 blocks conversion of β- To α-intercalated cells and induces distal renal tubular acidosis

AU - Gao, Xiaobo

AU - Eladari, Dominique

AU - Leviel, Francoise

AU - Tew, Ben Yi

AU - Miró-Julià, Cristina

AU - Cheema, Faisal

AU - Miller, Lance

AU - Nelson, Raoul

AU - Pǎunescu, Teodor G.

AU - McKee, Mary

AU - Brown, Dennis

AU - Al-Awqati, Qais

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