Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 13, Issue 11, Pages 1303-1311Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728220903260807
Keywords
coagulation; fibrosis; hypertension; inflammation; metabolic syndrome
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Funding
- Deutsche Forschungsgerneinschaft [GRK 1302, G0709/4-4]
- National Institutes of Health (NIH) [DK56248, DK28602]
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Compelling evidence is accumulating indicating a pathophysiological role of the serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in the development and complications of diabetes. SGK1 is ubiquitously expressed with exquisitely high transcriptional volatility. Stimulators of SGK1 expression include hyperglycemia, cell shrinkage, ischemia, glucocorticoids and mineralocorticoids. SGK1 is activated by insulin and growth factors via PI3K, 3-phosphoinositide dependent kinase PDK1 and mTOR. SGK1 activates ion channels (including ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and CLCKa/Barttin), carriers (including NCC, NKCC, NHE3, SGLT1 and EAAT3), and the Na+/K+-ATPase. It regulates the activity of several enzymes (e.g., glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g., forkhead-transcription-factor FOXO3a, beta-catenin and NF-kappa B). A common SGK1 gene variant (similar to 3 - 5% prevalence in Caucasians, similar to 10% in Africans) is associated with increased blood pressure, obesity and type 2 diabetes. in patients suffering from type 2 diabetes, SGK1 presumably contributes to fluid retention and hypertension, enhanced coagulation and increased deposition of matrix proteins leading to tissue fibrosis such as diabetic nephropathy. Accordingly, targeting SGK1 may favourably influence occurrence and course of type 2 diabetes.
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