SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction

J Am Soc Nephrol. 2010 Nov;21(11):1868-77. doi: 10.1681/ASN.2009121295. Epub 2010 Sep 2.


Polymorphisms in the gene encoding sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) associate with hypertension susceptibility in humans. SPAK interacts with WNK kinases to regulate the Na(+)-K(+)-2Cl(-) and Na(+)-Cl(-) co-transporters [collectively, N(K)CC]. Mutations in WNK1/4 and N(K)CC can cause changes in BP and dyskalemia in humans, but the physiologic role of SPAK in vivo is unknown. We generated and analyzed SPAK-null mice by targeting disruption of exons 9 and 10 of SPAK. Compared with SPAK(+/+) littermates, SPAK(+/-) mice exhibited hypotension without significant electrolyte abnormalities, and SPAK(-/-) mice not only exhibited hypotension but also recapitulated Gitelman syndrome with hypokalemia, hypomagnesemia, and hypocalciuria. In the kidney tissues of SPAK(-/-) mice, the expression of total and phosphorylated (p-)NCC was markedly decreased, but that of p-OSR1, total NKCC2, and p-NKCC2 was significantly increased. We observed a blunted response to thiazide but normal response to furosemide in SPAK(-/-) mice. In aortic tissues, total NKCC1 expression was increased but p-NKCC1 was decreased in SPAK-deficient mice. Both SPAK(+/-) and SPAK(-/-) mice had impaired responses to the selective α(1)-adrenergic agonist phenylephrine and the NKCC1 inhibitor bumetanide, suggesting that impaired aortic contractility may contribute to the hypotension of SPAK-null mice. In summary, SPAK-null mice have defects of NCC in the kidneys and NKCC1 in the blood vessels, leading to hypotension through renal salt wasting and vasodilation. SPAK may be a promising target for antihypertensive therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / physiopathology*
  • Blood Pressure / physiology
  • Disease Models, Animal
  • Diuretics / pharmacology
  • Female
  • Furosemide / pharmacology
  • Gitelman Syndrome / metabolism*
  • Gitelman Syndrome / physiopathology*
  • Hydrochlorothiazide / pharmacology
  • Hypotension / metabolism
  • Hypotension / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Serine-Threonine Kinases / deficiency*
  • Protein Serine-Threonine Kinases / genetics
  • Sodium Chloride Symporters / metabolism
  • Sodium-Potassium-Chloride Symporters / metabolism
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology*


  • Diuretics
  • Sodium Chloride Symporters
  • Sodium-Potassium-Chloride Symporters
  • Hydrochlorothiazide
  • Furosemide
  • Stk39 protein, mouse
  • OXSR1 protein, mouse
  • Protein Serine-Threonine Kinases