SGK1 stimulates ENaC, ROMK1, Na⁺/K⁺ ATPase and presumably NCC. Mice deficient in SGK1 (sgk^-/-) show a compensated salt loosing phenotype with increased plasma aldosterone levels. The present experiments aimed at identifying compensatory mechanisms of Na⁺ transport in sgk^-/- mice by analyzing the responses to different diuretics. Sgk1^-/- mice and their wild type littermates (sgk1^+/+) underwent diuretic treatment with triamterene (200mg/l), furosemide (125mg/l), hydrochlorothiazide (400mg/l) and canrenoate (800mg/l) delivered in the drinking water over 8 days. Renal SGK1 expression under the different treatments was studied using quantitative RT-PCR. Diuretic treatment increased SGK1 transcript levels in the kidney of wild-type sgk1^+/+ mice. Fluid and thus drug intake were not significantly different between genotypes. The responses to furosemide, hydrochlorothiazide or canrenoate were not different between sgk1^+/+ and sgk1^-/- mice and were accompanied by moderate increases in plasma aldosterone and urea concentrations. However, treatment with triamterene led to severe, eventually lethal, salt wasting, body weight loss, increase of plasma aldosterone, urea and K⁺ concentrations in sgk1^-/- mice, an effect significantly less pronounced in sgk1^+/+ animals. In conclusion, SGK1 is critically required for diuretic tolerance to ENaC blockade by triamterene. Moreover, the observations confirm the impaired kaliuretic potency of sgk1^-/- mice.