Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway
| Autor: | Lang, Florian, Pearce, David |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Kidney Disease
epithelial Na+ channel ENaC Clinical Sciences Mechanistic Target of Rapamycin Complex 1 Protein Serine-Threonine Kinases Kidney Cardiovascular Immediate-Early Proteins Animals Humans 2.1 Biological and endogenous factors Obesity Aetiology Epithelial Sodium Channels Nutrition aldosterone glucocorticoids TOR Serine-Threonine Kinases Nuclear Proteins Nephrons Urology & Nephrology Up-Regulation mammalian target of rapamycin mTOR Gene Expression Regulation Multiprotein Complexes Hypertension renal Na+ excretion |
| Zdroj: | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association-European Renal Association, vol 31, iss 2 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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