title: Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARgamma agonist pioglitazone.
abstract: PPARgamma-agonists enhance insulin sensitivity and improve glucose utilization in diabetic patients. Adverse effects of PPARgamma-agonists include volume retention and edema formation. Recent observations pointed to the ability of PPARgamma 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 PPARgamma agonists. To test this hypothesis, food containing the PPARgamma 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-/- 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+/+ mice. According to Evans Blue distribution, pioglitazone increased plasma volume only in sgk1+/+ mice (from 50.9+/-3.9 to 63.7+/-2.5 microl/g bw) but not in sgk-/- mice (from 46.8+/-3.8 to 48.3+/-5.2 microl/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 PPARgamma agonist pioglitazone.
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Ferruh
authors.initials: F
authors.lastname: Artunc
authors.forename: Diana
authors.initials: D
authors.lastname: Sandulache
authors.forename: Omaima
authors.initials: O
authors.lastname: Nasir
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.forename: Björn
authors.initials: B
authors.lastname: Friedrich
authors.forename: Norbert
authors.initials: N
authors.lastname: Beier
authors.forename: Edith
authors.initials: E
authors.lastname: Dicks
authors.forename: Sven
authors.initials: S
authors.lastname: Pötzsch
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Blazer-Yost
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Scholz
authors.forename: Teut
authors.initials: T
authors.lastname: Risler
authors.forename: Dietmar
authors.initials: D
authors.lastname: Kuhl
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008901:Mineralocorticoids / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D010953:Plasma Volume / Q000187:drug effects* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents; D017874:Immediate-Early Proteins; D008901:Mineralocorticoids; D047495:PPAR gamma; D000077205:Pioglitazone; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000099184:Serum-Glucocorticoid Regulated Kinases