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Deletion of hensin/DMBT1 blocks conversion of beta- to alpha-intercalated cells and induces distal renal tubular acidosis.

Gao, Xiaobo; Eladari, Dominique; Leviel, Francoise; Tew, Ben Yi; Miró-Julià, Cristina; Cheema, Faisal H; Cheema, Faisal; Miller, Lance; Nelson, Raoul; Paunescu, Teodor G; McKee, Mary; Brown, Dennis; Al-Awqati, Qais.
Proc Natl Acad Sci U S A; 107(50): 21872-7, 2010 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-21098262
Acid-base transport in the renal collecting tubule is mediated by two canonical cell types: the ß-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 ß-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 ß-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 ß-intercalated cell in ultrastructure, but does not express pendrin. Polymerization and deposition of hensin (in response to acidosis) requires the activation of ß1 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 ß- 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.
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