title: Renal tubular SGK1 deficiency causes impaired K+ excretion via loss of regulation of NEDD4-2/WNK1 and ENaC.
abstract: The stimulation of postprandial K(+) clearance involves aldosterone-independent and -dependent mechanisms. In this context, serum- and glucocorticoid-induced kinase (SGK)1, a ubiquitously expressed kinase, is one of the primary aldosterone-induced proteins in the aldosterone-sensitive distal nephron. Germline inactivation of SGK1 suggests that this kinase is fundamental for K(+) excretion under conditions of K(+) load, but the specific role of renal SGK1 remains elusive. To avoid compensatory mechanisms that may occur during nephrogenesis, we used inducible, nephron-specific Sgk1(Pax8/LC1) mice to assess the role of renal tubular SGK1 in K(+) regulation. Under a standard diet, these animals exhibited normal K(+) handling. When challenged by a high-K(+) diet, they developed severe hyperkalemia accompanied by a defect in K(+) excretion. Molecular analysis revealed reduced neural precursor cell expressed developmentally downregulated protein (NEDD)4-2 phosphorylation and total expression. γ-Epithelial Na(+) channel (ENaC) expression and α/γENaC proteolytic processing were also decreased in mutant mice. Moreover, with no lysine kinase (WNK)1, which displayed in control mice punctuate staining in the distal convoluted tubule and diffuse distribution in the connecting tubule/cortical colleting duct, was diffused in the distal convoluted tubule and less expressed in the connecting tubule/collecting duct of Sgk(Pax8/LC1) mice. Moreover, Ste20-related proline/alanine-rich kinase phosphorylation, and Na(+)-Cl(-) cotransporter phosphorylation/apical localization were reduced in mutant mice. Consistent with the altered WNK1 expression, increased renal outer medullary K(+) channel apical localization was observed. In conclusion, our data suggest that renal tubular SGK1 is important in the regulation of K(+) excretion via the control of NEDD4-2, WNK1, and ENaC.
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; National Centre of Competence in Research "Kidney.ch," Lausanne, Switzerland.
authors.forename: Lama
authors.initials: L
authors.lastname: Al-Qusairi
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; National Centre of Competence in Research "Kidney.ch," Lausanne, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Basquin
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania;
authors.forename: Ankita
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
authors.forename: Matteo
authors.initials: M
authors.lastname: Stifanelli
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
authors.forename: Renuga Devi
authors.initials: RD
authors.lastname: Rajaram
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
authors.forename: Anne
authors.initials: A
authors.lastname: Debonneville
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
authors.forename: Izabela
authors.initials: I
authors.lastname: Nita
authors.affiliation: Service of Nephrology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
authors.forename: Marc
authors.initials: M
authors.lastname: Maillard
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland; and National Centre of Competence in Research "Kidney.ch," Lausanne, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine and Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania;
authors.forename: Arohan R
authors.initials: AR
authors.lastname: Subramanya
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; National Centre of Competence in Research "Kidney.ch," Lausanne, Switzerland olivier.staub@unil.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Staub
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D004032:Diet; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000172:deficiency* / Q000235:genetics*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D011188:Potassium / Q000652:urine*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000276:immunology; D017419:Potassium, Dietary / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D019138:Antibodies, Blocking; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D015778:Minor Histocompatibility Antigens; D000075702:Nedd4 Ubiquitin Protein Ligases; D011188:Potassium; D024661:Potassium Channels, Inwardly Rectifying; D017419:Potassium, Dietary; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099184:Serum-Glucocorticoid Regulated Kinases; C510693:Kcnj1 protein, mouse; C000618461:Nedd4l protein, mouse; C498744:Wnk1 protein, mouse
keywords: aldosterone; epithelial Na+ channel; epithelial transport; neural precursor cell expressed developmentally downregulated protein 4-2; phosphorylation; potassium; serum- and glucocorticoid-induced kinase 1; ubiquitylation; with no lysine kinase 1