ArticleJournal of the American Society of Nephrology : JASN2015
Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters.
Article in Journal of the American Society of Nephrology : JASN, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 74 citations in OpenAlex.
- No lysine? No problem: the surprising roles of WNK kinases in physiology and disease.The Biochemical journal · 2026Review
- AMPK-OXSR1 signaling coordinates proximal tubular sodium transport and is modulated by canagliflozin.Frontiers in endocrinology · 2026Article
- Peroxiredoxin 5 Acts as a Negative Regulator of the Sodium-Chloride Cotransporter Involved in Alleviating Angiotensin II-Induced Hypertension.Antioxidants (Basel, Switzerland) · 2025Article
- Inflammation and vasopressin hypersecretion in aging.Frontiers in endocrinology · 2025Review
- Sodium Chloride Cotransporter in Hypertension.Biomedicines · 2024Review
- Article
- Modulation of Cerebrospinal Fluid Dysregulation via a SPAK and OSR1 Targeted Framework Nucleic Acid in Hydrocephalus.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Article
- Review
- Inhibition of WNK Kinases in NK Cells Disrupts Cellular Osmoregulation and Control of Tumor Metastasis.Journal of innate immunity · 2024Article
- Article
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
- CCT and CCT-Like Modular Protein Interaction Domains in WNK Signaling.Molecular pharmacology · 2022Review
- NCC regulation by WNK signal cascade.Frontiers in physiology · 2022Review
- Repurposing the PDMA-approved drugs in Japan using an insect model of staphylococcal infection.FEMS microbes · 2022Article
- The Less Well-Known Little Brothers: The SLC9B/NHA Sodium Proton Exchanger Subfamily-Structure, Function, Regulation and Potential Drug-Target Approaches.Frontiers in physiology · 2022Review
- Phosphorylated WNK kinase networks in recoded bacteria recapitulate physiological function.Cell reports · 2021Article
- Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension.Acta pharmaceutica Sinica. B · 2021Review
- WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension.Acta pharmacologica Sinica · 2021Review
- Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Upon activation by with-no-lysine kinases, STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) phosphorylates and activates SLC12A transporters such as the Na(+)-Cl(-) cotransporter (NCC) and Na(+)-K(+)-2Cl(-) cotransporter type 1 (NKCC1) and type 2 (NKCC2); these transporters have important roles in regulating BP through NaCl reabsorption and vasoconstriction. SPAK knockout mice are viable and display hypotension with decreased activity (phosphorylation) of NCC and NKCC1 in the kidneys and aorta, respectively. Therefore, agents that inhibit SPAK activity could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we developed a new ELISA-based screening system to find novel SPAK inhibitors and screened >20,000 small-molecule compounds. Furthermore, we used a drug repositioning strategy to identify existing drugs that inhibit SPAK activity. As a result, we discovered one small-molecule compound (Stock 1S-14279) and an antiparasitic agent (Closantel) that inhibited SPAK-regulated phosphorylation and activation of NCC and NKCC1 in vitro and in mice. Notably, these compounds had structural similarity and inhibited SPAK in an ATP-insensitive manner. We propose that the two compounds found in this study may have great potential as novel antihypertensive drugs.
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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.