Deletion of hensin/DMBT1 blocks conversion of β- to α-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.

Collecting Duct Intercalated Cell Function and Regulation

“…Moreover, mice with a hensin defect in intercalated cells indeed developed metabolic acidosis. In this mouse model, intercalated cells in the cortex had a type B phenotype (44). Interestingly, the hensin-deficient mice had modified the phenotype of medullary epithelial cells.…”

“…In some of these studies carried out in the rabbit model, adaptation to acidosis was not accompanied by changes in the number of intercalated cells but rather by a change from type B to type A intercalated cells (7,43). The transition process from type B to type A intercalated cell depends on the basolateral deposition of the extracellular matrix proteins hensin (DMBT1), galectin 3, and other proteins (7,44). Overall, induction of chronic metabolic acidosis increases the proportion of type A intercalated cells while metabolic alkalosis causes an increase of type B intercalated cells (7,45,46).…”

Acid-Base Homeostasis

“…Remodeling of IC morphology, number (relative numbers of A, B, and non-A, non-B ICs), and distribution of various transporters has also been characterized (64,65). The matrix protein hensin is a key mediator of this remodeling.…”

Specification of ion transport cells in theXenopuslarval skin

“…This suggests that the differentiation of IC subtypes could rely on phenotypic plasticity; however, the mechanisms underlying IC subtype specification are largely unknown. The extracellular matrix molecule hensin/dmbt1 has been proposed to mediate subtype interconversion in pH shift experiments on cultured cells (Al-Awqati, 1996) and in vivo (Schwartz et al, 2002;Gao et al, 2010) but the transcriptional mechanisms underlying its activities are still unclear. Moreover, little is known about when ICs acquire subtype properties during their differentiation, or the developmental mechanisms that lead to the differential localization of the H + v-ATPase or expression of ae1 and pendrin during subtype specification (Hiatt et al, 2010).…”