New insights into the role of serum- and glucocorticoid-inducible kinase SGK1 in the regulation of renal function and blood pressure.
OBJECTIVE
The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. We describe recent advances in our understanding of SGK1 function in the regulation of renal function and blood pressure.


RESULTS
Thiazolidinediones, i.e. activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), upregulate SGK1 and ENaC mRNA expression and increase cell-surface expression of ENaC alpha in a human cortical-collecting-duct cell line. cAMP/protein kinase A can induce phosphorylation and inhibition of Nedd4-2-independent of SGK1. Part of ENaC stimulation by SGK1 appears dependent on a SGK1 consensus motif in ENaC alpha and independent of Nedd4-2. SGK1-dependent upregulation of Na+ reabsorption in ASDN contributes to upregulation of renal K+ excretion. In oocytes, SGK1 activates various renal transport proteins including Na+/glucose cotransporter SGLT1, Na+-coupled dicarboxylate transporter NaDC-1, epithelial Ca+ channel TRPV5, renal outer medullary K+ channel ROMK and voltage gated K+ channels KCNE1/KCNQ1 and Kv1.3. A variant of the SGK1 gene associates with increased blood pressure and body mass index.


CONCLUSIONS
PPAR gamma activators may increase renal Na reabsorption by stimulating SGK1 and ENaC. Nedd4-2 integrates influences of cAMP/protein kinase A and SGK1. SGK1 can activate ENaC in part directly and independent of Nedd4-2. K+ homeostasis requires SGK1-dependent Na+ reabsorption in ASDN. SGK1 may affect renal transport mechanisms beyond Na+ reabsorption and K+ secretion in ASDN. Polymorphisms of SGK1 may be relevant to the pathophysiology of hypertension and other diseases.
Vallon
Volker
V
Department of Medicine, University of California San Diego & VA San Diego Health Care System, CA 92161, USA. vvallon@ucsd.edu
Lang
Florian
F
D001794:Blood Pressure / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins; D007686:Kidney Tubules, Distal / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D011110:Polymorphism, Genetic; D011188:Potassium / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
D017868:Cyclic AMP-Dependent Protein Kinases; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D011188:Potassium; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D015222:Sodium Channels; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C465283:WWP2 protein, human