The mineralocorticoid hormone aldosterone controls blood pressure largely by regulating Na⁺ reabsorption across epithelial cells of the aldosterone-sensitive distal nephron (ASDN). The epithelial Na⁺ channel (ENaC) of the ASDN is activated by aldosterone partly via induction of Sgk1 that prevents ENaC ubiquitylation by Nedd4-2. We identified early aldosterone-regulated mRNAs in mouse distal nephron by Affymetrix^TM Gene Chip analysis. Next to Sgk1 we detected ca 20 other mRNAs showing within 1 hour an at least 2-fold regulation, amongst them an induced deubiquitylating enzyme, Usp-P. We showed, using two-electrode voltage-clamp, that coexpression of Usp-P stimulates ENaC function in X. laevis oocytes. This effect depends on the protease activity of Usp-P, since it was inhibited by substitution of one essential amino acid of its catalytic core. By using Hek293 cells it could be shown that Usp-P deubiquitylates ENaC. Usp-G, another aldosterone regulated deubiquitylating enzyme, increases the Na,K-ATPase current in X. laevis oocytes. This effect is higher on the current of exogenously expressed Na,K-ATPase than on that of endogenous pumps. The observation, that aldosterone-induced Usp's stimulate the function of ENaC and Na,K-ATPase reinforces the concept, that ubiquitylation and deubiquitylation reactions play a central role in transepithelial Na⁺ transport regulation.