The proximal tubule reabsorbs most of the filtered bicarbonate which is mediated in large part by Na(+)/H(+) exchange (NHE). We have previously demonstrated that there is an isoform switch during postnatal maturation from NHE8 to NHE3 that is concordant with the postnatal increase in serum glucocorticoid levels. To examine if glucocorticoids may be responsible for this isoform switch, we administered dexamethasone daily to mice at 7-10 days of age, a time prior to the normal isoform switch. We show that compared to vehicle treated controls, dexamethasone caused a premature increase in renal NHE3 and decrease in NHE8 mRNA, total protein and brush border membrane protein abundance. To examine if there was a direct epithelial action of dexamethasone on NHE8, we studied NRK cells in vitro which express NHE8 on their apical membrane. Dexamethasone decreased NHE8 mRNA, total protein, and apical protein abundance. Dexamethasone also decreased Na(+)/H(+) exchanger activity. These studies provide evidence that glucocorticoids may play a role in the developmental isoform switch from NHE8 to NHE3 and cause a decrease in NHE8 expression and activity.