SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.

Abstract

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.

• Authors: Sung-Sen Yang, Yi-Fen Lo, Chin-Chen Wu, Shu-Wha Lin, Chien-Ju Yeh, Pauling Chu, Huey-Kang Sytwu, Shinichi Uchida, Sei Sasaki, Shih-Hua Lin
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 21 Issue 11 Pg. 1868-77 (Nov 2010) ISSN: 1533-3450 [Electronic] United States
• PMID: 20813865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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