SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction
Journal
Journal of the American Society of Nephrology
Journal Volume
21
Journal Issue
11
Pages
1868_1877
Date Issued
2010
Author(s)
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 α1-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. Copyright ? 2010 by the American Society of Nephrology.
SDGs
Other Subjects
bumetanide; furosemide; hydrochlorothiazide; phenylephrine; prolylalanine rich kinase; protein kinase; sodium potassium chloride cotransporter; unclassified drug; animal experiment; animal model; aorta constriction; article; enzyme blood level; enzyme phosphorylation; exon; female; Gitelman syndrome; hypocalciuria; hypokalemia; hypomagnesemia; hypotension; kidney parenchyma; kidney tubule; male; mouse; nonhuman; priority journal; protein expression; vasoconstriction; Animals; Aorta; Blood Pressure; Disease Models, Animal; Diuretics; Female; Furosemide; Gitelman Syndrome; Hydrochlorothiazide; Hypotension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Protein-Serine-Threonine Kinases; Sodium Chloride Symporters; Sodium-Potassium-Chloride Symporters; Transcription Factors; Vasoconstriction
Type
journal article