Therapeutic potential of serum and glucocorticoid inducible kinase inhibition

Expert Opin Investig Drugs. 2013 Jun;22(6):701-14. doi: 10.1517/13543784.2013.778971. Epub 2013 Mar 19.

Abstract

Introduction: Expression of serum-and-glucocorticoid-inducible kinase-1 (SGK1) is low in most cells, but dramatically increases under certain pathophysiological conditions, such as glucocorticoid or mineralocorticoid excess, inflammation with TGFβ release, hyperglycemia, cell shrinkage and ischemia. SGK1 is activated by insulin and growth factors via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase and mammalian target of rapamycin. SGK1 sensitive functions include activation of ion channels (including epithelial Na(+) channel ENaC, voltage gated Na(+) channel SCN5A transient receptor potential channels TRPV4 - 6, Ca(2+) release activated Ca(2+) channel Orai1/STIM1, renal outer medullary K(+) channel ROMK, voltage gated K(+) channels KCNE1/KCNQ1, kainate receptor GluR6, cystic fibrosis transmembrane regulator CFTR), carriers (including Na(+),Cl(-) symport NCC, Na(+),K(+),2Cl(-) symport NKCC, Na(+)/H(+) exchangers NHE1 and NHE3, Na(+), glucose symport SGLT1, several amino acid transporters), and Na(+)/K(+)-ATPase. SGK1 regulates several enzymes (e.g., glycogen synthase kinase-3, ubiquitin-ligase Nedd4-2) and transcription factors (e.g., forkhead transcription factor 3a, β-catenin, nuclear factor kappa B).

Areas covered: The phenotype of SGK1 knockout mice is mild and SGK1 is apparently dispensible for basic functions. Excessive SGK1 expression and activity, however, contributes to the pathophysiology of several disorders, including hypertension, obesity, diabetes, thrombosis, stroke, fibrosing disease, infertility and tumor growth. A SGK1 gene variant (prevalence ∼ 3 - 5% in Caucasians and ∼ 10% in Africans) is associated with hypertension, stroke, obesity and type 2 diabetes. SGK1 inhibitors have been developed and shown to reduce blood pressure of hyperinsulinemic mice and to counteract tumor cell survival.

Expert opinion: Targeting SGK1 may be a therapeutic option in several clinical conditions, including metabolic syndrome and tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drug Design
  • Gene Expression Regulation
  • Genetic Variation
  • Humans
  • Immediate-Early Proteins / antagonists & inhibitors*
  • Immediate-Early Proteins / genetics
  • Mice
  • Mice, Knockout
  • Molecular Targeted Therapy*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics

Substances

  • Immediate-Early Proteins
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase