期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 50, 页码 21872-21877出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1010364107
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases [20999]
- American Heart Association
- Fondation Leducq
- l'Agence Nationale de la Recherche [PHYSIO 2007-RPV07084]
- National Institutes of Health [R37 DK42956]
- Boston Area Diabetes and Endocrinology Center [DK-57521]
- MGH Center for the Study of Inflammatory Bowel Disease [DK-43341]
- Spanish Ministry of Education [FPU AP2007-02223]
- [DK-73266]
Acid-base transport in the renal collecting tubule is mediated by two canonical cell types: the beta-intercalated cell secretes HCO3 by an apical Cl:HCO3 named pendrin and a basolateral vacuolar (V)-ATPase. Acid secretion is mediated by the alpha-intercalated cell, which has an apical V-ATPase and a basolateral Cl:HCO3 exchanger (kAE1). We previously suggested that the beta-cell converts to the alpha-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 alpha-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 beta-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 beta-intercalated cell in ultrastructure, but does not express pendrin. Polymerization and deposition of hensin (in response to acidosis) requires the activation of beta 1 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 beta- to alpha-intercalated cells is a manifestation of terminal differentiation, the present results demonstrate that this differentiation proceeds from HCO3 secreting to acid secreting phenotypes, a process that requires deposition of hensin in the ECM.
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