title: Deletion of hensin/DMBT1 blocks conversion of beta- to alpha-intercalated cells and induces distal renal tubular acidosis.
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- to α-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.
authors.affiliation: Department of Medicine and Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Gao
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
authors.forename: Francoise
authors.initials: F
authors.lastname: Leviel
authors.forename: Ben Yi
authors.initials: BY
authors.lastname: Tew
authors.forename: Cristina
authors.initials: C
authors.lastname: Miró-Julià
authors.forename: Faisal H
authors.initials: FH
authors.lastname: Cheema
authors.forename: Faisal
authors.initials: F
authors.lastname: Cheema
authors.forename: Lance
authors.initials: L
authors.lastname: Miller
authors.forename: Raoul
authors.initials: R
authors.lastname: Nelson
authors.forename: Teodor G
authors.initials: TG
authors.lastname: Paunescu
authors.forename: Mary
authors.initials: M
authors.lastname: McKee
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.forename: Qais
authors.initials: Q
authors.lastname: Al-Awqati
mesh_terms: D000141:Acidosis, Renal Tubular / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D006863:Hydrogen-Ion Concentration; D019012:Integrin beta1 / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D000076988:Sulfate Transporters; D025521:Tumor Suppressor Proteins
chemical_list: D027321:Anion Transport Proteins; D001639:Bicarbonates; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C114202:Dmbt1 protein, mouse; D019012:Integrin beta1; D009077:Mucins; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D025521:Tumor Suppressor Proteins