Steroid hormone release as well as renal water and electrolyte excretion of mice expressing PKB/SGK-resistant GSK3.
Insulin and insulin-like growth factor (IGF1) participate in the regulation of renal electrolyte excretion. Insulin- and IGF1-dependent signaling includes phosphatidylinositide-3 (PI3)-kinase, phosphoinositide-dependent kinase PDK1 as well as protein kinase B (PKB) and serum and glucocorticoid inducible kinase (SGK) isoforms, which in turn phosphorylate and thus inhibit glycogen synthase kinase GSK3alpha,beta. Replacement of the serines in the PKB/SGK consensus sequences by alanine (gsk3 ( KI )) confers resistance of GSK3 to PKB/SGK. To explore the role of PKB/SGK-dependent inhibition of GSK3 in the regulation of water/electrolyte metabolism, mice carrying the PKB/SGK resistant mutant (gsk3 ( KI )) were compared to their wild-type littermates (gsk3 ( WT ) ). Body weight was similar in gsk3 ( KI ) and gsk3 ( WT ) mice. Plasma aldosterone at 10 A.M: . and corticosterone concentrations at 5 P.M: . were significantly lower, but 24-h urinary aldosterone was significantly higher, and corticosterone excretion tended to be higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. Food and water intake, fecal excretion, glomerular filtration rate, urinary flow rate, urine osmolarity, as well as urinary Na+, K+, urea excretion were significantly larger, and plasma Na+, urea, but not K+ concentration, were significantly lower in gsk3 ( KI ) than in gsk3 ( WT ) mice. Body temperature was significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. When allowed to choose between tap water and saline, gsk3 ( WT ) mice drank more saline, whereas gsk3 ( KI ) mice drank similar large volumes of tap water and saline. During high-salt diet, urinary vasopressin excretion increased to significantly higher levels in gsk3 ( KI ) than in gsk3 ( WT ) mice. After water deprivation, body weight decreased faster in gsk3 ( KI ) than in gsk3 ( WT ) mice. Blood pressure, however, was significantly higher in gsk3 ( KI ) than in gsk3 ( WT ) mice. The observations disclose a role of PKB/SGK-dependent GSK3 activity in the regulation of steroid hormone release, renal water and electrolyte excretion and blood pressure control.
Boini
Krishna M
KM
Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
Bhandaru
Madhuri
M
Mack
Andreas
A
Lang
Florian
F
D000450:Aldosterone / Q000097:blood / Q000652:urine; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004326:Drinking / Q000235:genetics; D004435:Eating / Q000235:genetics; D004573:Electrolytes / Q000097:blood / Q000378:metabolism* / Q000652:urine; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006400:Hematocrit; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011188:Potassium / Q000097:blood / Q000652:urine; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012079:Renal Circulation / Q000502:physiology; D012964:Sodium / Q000097:blood / Q000652:urine; D013256:Steroids / Q000378:metabolism*; D014563:Urodynamics / Q000502:physiology; D014867:Water / Q000378:metabolism*
D004573:Electrolytes; D013256:Steroids; D014867:Water; D000450:Aldosterone; D003907:Dexamethasone; D012964:Sodium; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D011188:Potassium