Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype.
The expression of the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by mineralocorticoids and, in turn, upregulates the renal epithelial Na(+) channel (ENaC). Total inactivation of Sgk1 has been associated with transient urinary Na(+) wasting with a low-Na(+) diet, while the aldosterone-mediated ENaC channel activation was unchanged in the collecting duct. Since Sgk1 is ubiquitously expressed, we aimed to study the role of renal Sgk1 and generated an inducible kidney-specific knockout (KO) mouse. We took advantage of the previously described TetOn/CreLoxP system, in which rtTA is under the control of the Pax8 promotor, allowing inducible inactivation of the floxed Sgk1 allele in the renal tubules (Sgk1fl/fl/Pax8/LC1 mice). We found that under a standard Na(+) diet, renal water and Na(+)/K(+) excretion had a tendency to be higher in doxycycline-treated Sgk1 KO mice compared with control mice. The impaired ability of Sgk1 KO mice to retain Na(+) increased significantly with a low-salt diet despite higher plasma aldosterone levels. On a low-Na(+) diet, the Sgk1 KO mice were also hyperkaliuric and lost body weight. This phenotype was accompanied by a decrease in systolic and diastolic blood pressure. At the protein level, we observed a reduction in phosphorylation of the ubiquitin protein-ligase Nedd4-2 and a decrease in the expression of the Na(+)-Cl(-)-cotransporter (NCC) and to a lesser extent of ENaC.
Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 27, Lausanne, Switzerland.
Nourdine
N
Faresse
Dagmara
D
Lagnaz
Anne
A
Debonneville
Adil
A
Ismailji
Marc
M
Maillard
Geza
G
Fejes-Toth
Aniko
A
Náray-Fejes-Tóth
Olivier
O
Staub
D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004039:Diet, Sodium-Restricted; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000096:biosynthesis; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D011188:Potassium / Q000097:blood / Q000652:urine; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012964:Sodium / Q000097:blood / Q000652:urine*; D049992:Sodium Chloride Symporters / Q000096:biosynthesis; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D011188:Potassium; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D049992:Sodium Chloride Symporters; D017673:Sodium Chloride, Dietary; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C000618461:Nedd4l protein, mouse