期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 311, 期 2, 页码 F330-F342出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00002.2016
关键词
aldosterone; epithelial transport; phosphorylation; potassium; ubiquitylation; serum- and glucocorticoid-induced kinase 1; neural precursor cell expressed developmentally downregulated protein 4-2; with no lysine kinase 1; epithelial Na+ channel
资金
- Swiss National Science Foundation [310030_159735, 310030_143929/1]
- National Centre of Competence in Research Swiss Kidney.ch
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-098145]
- Novartis Foundation
- fellowship of the Marie Curie cofunding International Fellowship Program on Integrative Kidney Physiology and Pathophysiology
- Swiss National Science Foundation (SNF) [310030_159735] Funding Source: Swiss National Science Foundation (SNF)
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 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. gamma-Epithelial Na+ channel (ENaC) expression and alpha/gamma ENaC 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.
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