Na⁺ re-absorption within the distal nephron determines the amount of Na⁺ lost in the urine and this process can be controlled by insulin, a hormone that activates phosphoinositide-3-kinase (PI3K) (Loffing and Korbmacher, 2009). The mechanism permitting this control is not well understood but data from several sources highlight the importance of serum and glucocorticoid-inducible kinase 1 (SGK1), a kinase activated by PI3K that can control the apical abundance of epithelial Na⁺ channels (ENaC) (Loffing and Korbmacher, 2009). However, studies of fisher rat thyroid cells expressing the ENaC subunits suggest that insulin-induced Na⁺ absorption depends upon protein kinase B (PKB, also known as Akt), another target of PI3K (Lee et al., 2007). The present study therefore explores the effects of Akt-I1/2, a compound reported to inhibit PKB selectively, upon insulin-induced Na⁺ transport in a cell line (mpkCCD) derived from the distal nephron (Bens et al., 1999). Transepithelial Na⁺ transport was studied using standard Ussing chamber techniques whilst changes in PKB activity were assessed using Western analysis to monitor the phosphorylation of PKB-Ser⁴⁷³, a residue critical to the PI3K-dependent activation of this kinase. Cellular SGK1 activity was monitored by assaying the phosphorylation of residues within an endogenous protein (n-myc downstream gene regulated protein 1, NDRG1-Thr^346/356/366) that are phosphorylated by SGK1 but not by other kinases (Murray et al., 2005). Data are mean ± s.e.m and values of n refer to the number of times a protocol was repeated using cells at different passage. Akt-I1/2 (1 µM, 60 min) caused ~25% inhibition of the amiloride-sensitive I_SC measured under basal conditions(Akt-I1/2: -15.8 ± 1.4 µA ^-2, solvent vehicle: -20.4 ± 1.0 µA ^-2, n = 15, P < 0.02, Student’s paired t test). Although insulin (20 nM, 60 min) consistently augmented this current, the response measured in Akt-I1/2-treated cells (ΔI_SC: -4.9 ± 1.9 µA cm^-2, n = 6) was only ~50% (P < 0.0001, Student’s t test) of control (ΔI_SC: -9.8 ± 1.4 µA cm^-2, n = 14). Insulin normally activated both PKB and SGK1 and, although Akt-I1/2 (1 µM) reduced the activation of PKB, this response was still seen in Akt-I1/2-treated cells (n = 9). Suprisingly, Akt-I1/2 also reduced the activation of SGK1 (n = 8). Experiments that explored the effects of higher concentrations of Akt-I1/2 (3 µM and 10 µM) revealed essentially complete inhibition of PKB at 10 µM (n = 6). However, at this concentration, Akt-I1/2 also prevented the activation of SGK1. Although Akt-I1/2 inhibits the insulin-induced increase in I_SC, this finding cannot be cited in support of the idea that PKB is central to the control of Na⁺ transport (Lee et al., 2007) since Akt-I1/2 does not inhibit PKB selectively under the present conditions.