ArticleJournal of the American Society of Nephrology : JASN2010
SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.
Article in Journal of the American Society of Nephrology : JASN, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 159 papers.
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Who cites it
159 citing papers in PubMed, 277 citations in OpenAlex.
- The WNK-OXSR1 osmosensing pathway mediates intestinal regeneration via Hippo-YAP signaling.The EMBO journal · 2026Article
- Central Osmolality Sensing for Arginine Vasopressin Release Is Mediated by WNK1-OSR1/SPAK-Kv3.1 Cascade.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Pharmacological inhibition of SPAK-NKCC1 complex attenuates astrogliosis and restores cerebral blood flow in a mouse model of VCID.Acta neuropathologica communications · 2025Article
- Calcium-binding protein 39 in with-no-lysine kinase signaling and the modulation of renal tubular transport.Current opinion in nephrology and hypertension · 2025Review
- Thick Ascending Limb Specific Inactivation of Myh9 and Myh10 Myosin Motors Results in Progressive Kidney Disease and Drives Sex-specific Cellular Adaptation in the Distal Nephron and Collecting Duct.Function (Oxford, England) · 2025Article
- Role of ENaC in gender-associated differences in blood pressure.Iranian journal of basic medical sciences · 2025Article
- Familial Hyperkalemic Hypertension.Comprehensive Physiology · 2024Review
- Macrophage SPAK deletion limits a low potassium-induced kidney inflammatory program.American journal of physiology. Renal physiology · 2024Article
- Carotid artery vascular stenosis causes the blood-CSF barrier damage and neuroinflammation.Journal of neuroinflammation · 2024Article
- Role of calcineurin in regulating renal potassium (KActa physiologica (Oxford, England) · 2024Review
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.Nature communications · 2024Article
- Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Article
- Dysregulation of the WNK4-SPAK/OSR1 pathway has a minor effect on baseline NKCC2 phosphorylation.American journal of physiology. Renal physiology · 2024Article
- Update on NKCC2 regulation in the thick ascending limb (TAL) by membrane trafficking, phosphorylation, and protein-protein interactions.Frontiers in physiology · 2024Review
- The role of uromodulin in cardiovascular disease: a review.Frontiers in cardiovascular medicine · 2024Review
- Insights into the diverse mechanisms and effects of variant CUL3-induced familial hyperkalemic hypertension.Cell communication and signaling : CCS · 2023Review
- Kidney and blood pressure regulation-latest evidence for molecular mechanisms.Clinical kidney journal · 2023Review
- Chloride Ions, Vascular Function and Hypertension.Biomedicines · 2022Review
99 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.