Journal Article

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

Florian Lang and David Pearce

in Nephrology Dialysis Transplantation

Volume 31, issue 2, pages 200-205
Published in print February 2016 | ISSN: 0931-0509
Published online July 2015 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfv270
Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway

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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

Journal Article.  4369 words.  Illustrated.

Subjects: Nephrology

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