title: Blocking the salt-inducible kinase 1 network prevents the increases in cell sodium transport caused by a hypertension-linked mutation in human alpha-adducin.
abstract: OBJECTIVE
  Because a newly described salt-inducible kinase 1 (SIK1) network is responsible for increases in active cell sodium transport in response to elevated intracellular sodium, we hypothesized that this network could mediate the effects of the mutant (hypertensive) form of alpha-adducin on Na,K-ATPase activity.
  
  
  METHODS
  Studies were performed in normotensive and hypertensive Milan rats and in a cell line of proximal tubule origin expressing transiently variants of alpha-adducin (human G460W/S586C; rat F316Y) that are associated with elevated blood pressure and result in increased Na,K-ATPase activity. Na,K-ATPase activity was determined as ouabain-sensitive rubidium transport.
  
  
  RESULTS
  SIK1 activity (T182 phosphorylation) was significantly elevated in renal proximal tubule cells from Milan hypertensive rats (carrying a alpha-adducin mutation) when compared with normotensive controls. Similarly, SIK1 activity (T182 phosphorylation) was elevated in a normal renal proximal tubule cell line when transfected with the alpha-adducin variant carrying the human hypertensive mutation. Blocking the SIK1 network using negative mutants as well as different stages of its activation pathway prevented the effects induced by the hypertensive alpha-adducin.
  
  
  CONCLUSIONS
  The SIK1 network may constitute an alternative target by which agents can modulate active sodium transport in renal epithelia and avoid the increases in systemic blood pressure that are associated with genetic mutations in the human alpha-adducin molecule.
authors: Membrane Signaling Networks, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors: Karin
authors: K
authors: Stenström
authors: Hiroshi
authors: H
authors: Takemori
authors: Giuseppe
authors: G
authors: Bianchi
authors: Adrian I
authors: AI
authors: Katz
authors: Alejandro M
authors: AM
authors: Bertorello
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells; D015971:Gene Expression Regulation, Enzymologic; D055786:Gene Knockout Techniques; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D009154:Mutation; D009893:Opossums; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014162:Transfection; D014655:Vascular Resistance / Q000235:genetics; D000099291:Adducins
chemical_list: D002148:Calmodulin-Binding Proteins; D010749:Phosphoprotein Phosphatases; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D000099291:Adducins; C509080:SIK1 protein, human