To study the role of serum and glucocorticoid-inducible kinase-1 (SGK1) in mammalian cells, we compared Na(+) transport rates in wild-type (WT) M1 cortical collecting duct cells with M1 populations stably expressing human full-length SGK1, NH(2)-terminal truncated (DeltaN-60) SGK1, "kinase-dead" (K127M) SGK1, and cells that have downregulated levels of SGK1 mRNA (antisense SGK1). Basal rates of transepithelial Na(+) transport were highest in full-length SGK1 populations, compared among the above populations. Dexamethasone treatment increased Na(+) transport in WT and full-length SGK1 cells 2.7- and 2-fold, respectively. Modest stimulation of Na(+) absorption was detected after dexamethasone treatment in DeltaN-60 SGK1 populations. However, DeltaN-60 SGK1 transport rates remained substantially lower than WT values. Importantly, a combination of high insulin, dexamethasone, and serum failed to significantly stimulate Na(+) transport in antisense or K127M SGK1 cells. Additionally, expression of antisense SGK1 significantly decreased transepithelial resistance values. Overall, we concluded that SGK1 is a critical component in corticosteroid-regulated Na(+) transport in mammalian cortical collecting duct cells. Furthermore, our data suggest that the NH(2) terminus of SGK1 may contain a Phox homology-like domain that may be necessary for effective Na(+) transport.