Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype

Am J Physiol Renal Physiol. 2012 Apr 15;302(8):F977-85. doi: 10.1152/ajprenal.00535.2011. Epub 2012 Feb 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / blood
  • Animals
  • Blood Pressure / physiology
  • Diet, Sodium-Restricted
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Epithelial Sodium Channels / biosynthesis
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Immediate-Early Proteins / physiology*
  • Kidney / metabolism
  • Kidney / physiology*
  • Mice
  • Mice, Knockout
  • Nedd4 Ubiquitin Protein Ligases
  • Phosphorylation
  • Potassium / blood
  • Potassium / urine
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Sodium / blood
  • Sodium / urine*
  • Sodium Chloride Symporters / biosynthesis
  • Sodium Chloride, Dietary / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Endosomal Sorting Complexes Required for Transport
  • Epithelial Sodium Channels
  • Immediate-Early Proteins
  • Sodium Chloride Symporters
  • Sodium Chloride, Dietary
  • Aldosterone
  • Sodium
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4l protein, mouse
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Potassium