Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Feb;31(2):200-5.
doi: 10.1093/ndt/gfv270. Epub 2015 Jul 9.

Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway

Florian Lang  1 , David Pearce  2
Affiliations
Review

Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway

Florian Lang et al. Nephrol Dial Transplant. 2016 Feb.

Abstract

The epithelial Na(+) channel (ENaC) is decisive for sodium reabsorption by the aldosterone-sensitive distal nephron (ASDN) of the kidney. ENaC is regulated by the serum- and glucocorticoid-inducible kinase 1 (SGK1), a kinase genomically upregulated by several hormones including glucocorticoids and mineralocorticoids. SGK1 is activated by the serine/threonine kinase mammalian target of rapamycin (mTOR) isoform mTORC2. SGK1 knockout (sgk1(-/-) mice) impairs renal Na(+) retention during salt depletion. The mTOR catalytic site inhibitor, PP242, but not mTORC1 inhibitor rapamycin, inhibits ENaC, decreases Na(+) flux in isolated perfused tubules and induces natriuresis in wild-type mice. PP242 does not lead to further impairment of Na(+) reabsorption in sgk1(-/-) mice. The mTORC2/SGK1 sensitive renal Na(+) retention leads to extracellular volume expansion with increase of blood pressure. A SGK1 gene variant (prevalence ∼ 3-5% in Caucasians, ∼ 10% in Africans) predisposes to hypertension, stroke, obesity and type 2 diabetes. Future studies will be required to define the role of mTORC2 in the regulation of further SGK1 sensitive transport proteins, such as further ion channels, carriers and the Na(+)/K(+)-ATPase. Moreover, studies are required disclosing the impact of mTORC2 on SGK1 sensitive disorders, such as hypertension, obesity, diabetes, thrombosis, stroke, inflammation, autoimmune disease, fibrosis and tumour growth.

Keywords: aldosterone; epithelial Na+ channel ENaC; glucocorticoids; mammalian target of rapamycin mTOR; renal Na+ excretion.

PubMed Disclaimer

Figures

FIGURE 1:
FIGURE 1:
Ion transport regulation by mTORC2 and SGK1 in renal principal cells. Principal cells respond to a variety of hormonal and non-hormonal stimuli to control Na+ and K+ transport. Aldosterone acts through the mineralocorticoid receptor (MR) to alter expression of various targets that modulate ion transport, notably the serum and glucocorticoid inducible kinase SGK1 and the small chaperone GILZ1 (Glucocorticoid-inducible leucine zipper protein 1). Other factors, such as insulin and angiotensin II act through the master kinases phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) to stimulate SGK1 activity. mTORC2 directly phosphorylates SGK1 in its hydrophobic motif, while PI3K acts through PI3K-dependent kinase to phosphorylate SGK1 in its activation loop. Only when phosphorylated at both these sites is SGK1 fully active. SGK1 phosphorylates a variety of proteins, notably the ubiquitin ligase, Nedd4-2, which is an ENaC inhibitor. SGK1 phosphorylation triggers interaction of Nedd4-2 with 14-3-3 proteins, hence reducing ENaC internalization and degradation. ENaC surface expression and activity are governed by a multiprotein ENaC Regulatory Complex (ERC, not shown for simplicity), whose assembly at the plasma membrane is orchestrated by the scaffold protein CNK3 (Connector Enhancer of Kinase Suppressor of Ras Isoform 3), which is also MR-regulated. Electrogenic Na+ reabsorption via ENaC is balanced by K+ secretion and Cl− reabsorption through multiple pathways (not shown). N4-2: Nedd4-2; PDK1: phosphoinositide-dependent kinase-1; PIP2: Phosphatidylinositol-4,5 bisphosphate; PIP3: phosphatidylinositol-3,4,5 trisphosphate; PH: pleckstrin homology domain; Ub: ubiquitin; RTK: receptor tyrosine kinase; GPCR: G-protein coupled receptor; Yellow circles: phosphate groups; other abbreviations as in text.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lang F, Stournaras C. Serum and glucocorticoid inducible kinase, metabolic syndrome, inflammation, and tumor growth. Hormones (Athens) 2013; 12: 160–171 - PubMed
    1. Pearce D, Soundararajan R, Trimpert C et al. . Collecting duct principal cell transport processes and their regulation. Clin J Am Soc Nephrol 2015; 10: 135–146 - PMC - PubMed
    1. Chraibi A, Renauld S. PPARgamma-induced stimulation of amiloride-sensitive sodium current in renal collecting duct principal cells is serum and insulin dependent. Cell Physiol Biochem 2014; 33: 581–593 - PubMed
    1. Pearce LR, Sommer EM, Sakamoto K et al. . Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem J 2011; 436: 169–179 - PubMed
    1. Lang F, Stournaras C, Alesutan I. Regulation of transport across cell membranes by the serum- and glucocorticoid-inducible kinase SGK1. Mol Membr Biol 2014; 31: 29–36 - PubMed

MeSH terms

Substances