The intercalated cell of the cortical collecting tubule exists in two functional and morphologic forms: alpha cells secrete acid, while beta cells secrete HCO(3). It was found that beta cells convert to alpha type when the animal ingests an acid diet or when isolated perfused tubules are exposed to acid. This conversion of cell phenotype requires the induction of new genes, accompanied by a change in cell shape, development of microvilli, and apical endocytosis. All of these changes are reminiscent of terminal differentiation in epithelial cells. Using a beta intercalated cell line, the cause of this phenotypic change was identified as a new extracellular matrix protein, which was termed hensin. When the action of hensin is blocked, the conversion of beta to alpha intercalated cells is prevented and the animals develop distal renal tubular acidosis. Hensin is expressed in most epithelia, and global knockout of hensin results in embryonic lethality at the time of development of the first columnar epithelium, the visceral endoderm. Furthermore, hensin also seems to be involved in the differentiation of transitional and perhaps stratified epithelia as well. A large number of human carcinomas have deletions in the human ortholog of hensin (DMBT1). Collectively, these studies demonstrate that hensin is a mediator of terminal differentiation in many epithelia.