Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

PPAR gamma-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPAR gamma-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPAR gamma agonists to enhance transcription of the serum and glucocorticoid-inducible kinase SGK1, a kinase that is genomically upregulated by mineralocorticoids and stimulates various renal channels and transporters including the renal epithelial Na+ channel ENaC. SGK1 has been proposed to mediate the volume retention after treatment with PPAR gamma agonists. To test this hypothesis, food containing the PPAR gamma agonist pioglitazone (0.02%, i.e., approximately 25 mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1(-/-,) n=12) and their wild-type littermates (sgk1(+/+) , n=12). According to in situ hybridization, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, treatment with pioglitazone significantly increased renal SGK1 mRNA and protein expression in sgk1(+/+) mice. The treatment increased body weight significantly in both, sgk1(+/+) mice (+2.2 +/- 0.3 g) and sgk(-/-) supercript stop mice (+1.3 +/- 0.2 g), and decreased hematocrit significantly in sgk1(+/+) mice (-6.5 +/- 1.0%) and sgk1(-/-) mice (-3.1 +/- 0.6%). Both effects were significantly (p < 0.05) more pronounced in sgk1(+/+) supercript stop mice. According to Evans Blue distribution, pioglitazone increased plasma volume only in sgk1(+/+) supercript stop mice (from 50.9 +/- 3.9 to 63.7 +/- 2.5 mu l/g bw) but not in sgk(-/-) supercript stop mice (from 46.8 +/- 3.8 to 48.3 +/- 5.2 mu l/g bw). Pioglitazone decreased aldosterone plasma levels and blood pressure and increased leptin plasma levels in both genotypes. We conclude that SGK1 contributes to but does not fully account for the volume retention during treatment with the PPAR gamma agonist pioglitazone.