Role of the WNK-activated SPAK kinase in regulating blood pressure.
Mutations within the with-no-K(Lys) (WNK) kinases cause Gordon's syndrome characterized by hypertension and hyperkalaemia. WNK kinases phosphorylate and activate the STE20/SPS1-related proline/alanine-rich kinase (SPAK) protein kinase, which phosphorylates and stimulates the key Na(+):Cl(-) cotransporter (NCC) and Na(+):K(+):2Cl(-) cotransporters (NKCC2) cotransporters that control salt reabsorption in the kidney. To define the importance of this pathway in regulating blood pressure, we generated knock-in mice in which SPAK cannot be activated by WNKs. The SPAK knock-in animals are viable, but display significantly reduced blood pressure that was salt-dependent. These animals also have markedly reduced phosphorylation of NCC and NKCC2 cotransporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in messenger RNA (mRNA) levels. On a normal Na(+)-diet, the SPAK knock-in mice were normokalaemic, but developed mild hypokalaemia when the renin-angiotensin system was activated by a low Na(+)-diet. These observations establish that SPAK plays an important role in controlling blood pressure in mammals. Our results imply that SPAK inhibitors would be effective at reducing blood pressure by lowering phosphorylation as well as expression of NCC and NKCC2. See accompanying Closeup by Maria Castañeda-Bueno and Gerald Gamba (DOI 10.1002/emmm.200900059).
Rafiqi
Fatema H
FH
University of Dundee, Scotland, UK.
Zuber
Annie Mercier
AM
Glover
Mark
M
Richardson
Ciaran
C
Fleming
Stewart
S
Jovanović
Sofija
S
Jovanović
Aleksandar
A
O'Shaughnessy
Kevin M
KM
Alessi
Dario R
DR
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006706:Homeostasis; D007668:Kidney / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism; D012492:Salts / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D016019:Survival Analysis; D027981:Symporters / Q000378:metabolism
D050505:Mutant Proteins; D011955:Receptors, Drug; D012492:Salts; C578715:Slc12a1 protein, mouse; C578875:Slc12a3 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases