Dataset Information

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.

SUBMITTER: Yang SS

PROVIDER: S-EPMC3014002 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.

Yang Sung-Sen SS Lo Yi-Fen YF Wu Chin-Chen CC Lin Shu-Wha SW Yeh Chien-Ju CJ Chu Pauling P Sytwu Huey-Kang HK Uchida Shinichi S Sasaki Sei S Lin Shih-Hua SH

Journal of the American Society of Nephrology : JASN 20100902 11

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. Comp ...[more]

PMID: 20813865

Similar Datasets

Project description:Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.

Dataset Information

SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.

Publications

SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets