Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARgamma agonist pioglitazone.
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.
Artunc
Ferruh
F
Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
Sandulache
Diana
D
Nasir
Omaima
O
Boini
Krishna M
KM
Friedrich
Björn
B
Beier
Norbert
N
Dicks
Edith
E
Pötzsch
Sven
S
Klingel
Karin
K
Amann
Kerstin
K
Blazer-Yost
Bonnie L
BL
Scholz
Wolfgang
W
Risler
Teut
T
Kuhl
Dietmar
D
Lang
Florian
F
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
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