The Cl-/HCO3- -exchanger AE1 is expressed in the kidney exclusively in type A acid-secretory intercalated cells along the collecting system. There AE1 is involved in the secretion of acid into urine via an apical H+-ATPase and absorption of newly formed bicarbonate. Loss of function due to mutations in man or genetic ablation in mice leads to a severe form of distal renal tubular acidosis. We examined the morphological alterations in the collecting duct using immunohistochemistry and EM. Using cell specific markers for intercalated cells (IC) (AE1, AE4, pendrin, a4 and B1 subunits of the vacuolar H+-ATPase) and principal cells (PC) (AQP2, calbindin), we found in wildtype animals normal separation of these markers into specific cells without overlap of markers for IC and PC. However, in AE1 deficient mice, about 10 % of all cells were devoid of all specific markers, whereas about 25 % showed an overlap of IC and PC markers. In addition, pendrin staining was observed in the medulla of AE1 KO but not in AE1 wildtype animals. Thus, loss of functional AE1 from the basolateral membrane causes a defect in the normal differentiation of cells in the collecting duct and this may contribute to the abnormal kidney function seen in patients or mice without functional AE1.