TY - JOUR
T1 - Renal tubular SGK1 deficiency causes impaired K+ excretion via loss of regulation of NEDD4-2/WNK1 and ENaC
AU - Al-Qusairi, Lama
AU - Basquin, Denis
AU - Roy, Ankita
AU - Stifanelli, Matteo
AU - Rajaram, Renuga Devi
AU - Debonneville, Anne
AU - Nita, Izabela
AU - Maillard, Marc
AU - Loffing, Johannes
AU - Subramanya, Arohan R.
AU - Staub, Olivier
N1 - Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - The stimulation of postprandial K+ clearance involves aldosterone-independent and -dependent mechanisms. In this context, serum- and glucocorticoidinduced 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 Sgk1Pax8/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 SgkPax8/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.
AB - The stimulation of postprandial K+ clearance involves aldosterone-independent and -dependent mechanisms. In this context, serum- and glucocorticoidinduced 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 Sgk1Pax8/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 SgkPax8/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.
KW - Aldosterone
KW - Epithelial Na channel
KW - Epithelial transport
KW - Neural precursor cell expressed developmentally downregulated protein 4-2
KW - Phosphorylation
KW - Potassium
KW - Serum- and glucocorticoid-induced kinase 1
KW - Ubiquitylation
KW - With no lysine kinase 1
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U2 - 10.1152/ajprenal.00002.2016
DO - 10.1152/ajprenal.00002.2016
M3 - Article
C2 - 27009335
AN - SCOPUS:84984650300
SN - 0363-6127
VL - 311
SP - F330-F342
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 2
ER -