ArticleThe Journal of biological chemistry2012
SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.
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Who cites it
96 citing papers in PubMed, 133 citations in OpenAlex.
- No lysine? No problem: the surprising roles of WNK kinases in physiology and disease.The Biochemical journal · 2026Review
- The kidney distal tubule potassium switch, modern diet and hypertension.Nature reviews. Nephrology · 2026Review
- Differential Assembly of Native Epithelial Sodium Channel Complexes Across Mouse Epithelial Tissues.Kidney360 · 2026Article
- LRBA organizes distinct vesicular trafficking systems in distal nephron segments for water and sodium conservation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Differential Assembly of Native ENaC Complexes Across Mouse Epithelial Tissues.bioRxiv : the preprint server for biology · 2026Article
- Mechanistic Target of Rapamycin Complex 1 in Distal Convoluted Tubule and Renal Potassium Handling.Journal of the American Society of Nephrology : JASN · 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
- Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates.The Journal of clinical investigation · 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
- Single-Nucleus RNA Sequencing Reveals Loss of Distal Convoluted Tubule 1 Renal Tubules in HIV Viral Protein R Transgenic Mice.The American journal of pathology · 2024Article
- Deletion of KS-WNK1 promotes NCC activation by increasing WNK1/4 abundance.American journal of physiology. Renal physiology · 2024Article
- A New Phase for WNK Kinase Signaling Complexes as Biomolecular Condensates.Physiology (Bethesda, Md.) · 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
- Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction.Nature communications · 2024Article
- Potassium-Switch Signaling Pathway Dictates Acute Blood Pressure Response to Dietary Potassium.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.Hypertension (Dallas, Tex. : 1979) · 2024Article
- Molecular Crowding: Physiologic Sensing and Control.Annual review of physiology · 2024Review
- Update on NKCC2 regulation in the thick ascending limb (TAL) by membrane trafficking, phosphorylation, and protein-protein interactions.Frontiers in physiology · 2024Review
36 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) and oxidative stress-related kinase (OSR1) activate the potassium-dependent sodium-chloride co-transporter, NKCC2, and thiazide-sensitive sodium-chloride cotransporter, NCC, in vitro, and both co-localize with a kinase regulatory molecule, Cab39/MO25α, at the apical membrane of the thick ascending limb (TAL) and distal convoluted tubule (DCT). Yet genetic ablation of SPAK in mice causes a selective loss of NCC function, whereas NKCC2 becomes hyperphosphorylated. Here, we explore the underlying mechanisms in wild-type and SPAK-null mice. Unlike in the DCT, OSR1 remains at the TAL apical membrane of KO mice where it is accompanied by an increase in the active, phosphorylated form of AMP-activated kinase. We found an alterative SPAK isoform (putative SPAK2 form), which modestly inhibits co-transporter activity in vitro, is more abundant in the medulla than the cortex. Thus, enhanced NKCC2 phosphorylation in the SPAK knock-out may be explained by removal of inhibitory SPAK2, sustained activity of OSR1, and activation of other kinases. By contrast, the OSR1/SPAK/M025α signaling apparatus is disrupted in the DCT. OSR1 becomes largely inactive and displaced from M025α and NCC at the apical membrane, and redistributes to dense punctate structures, containing WNK1, within the cytoplasm. These changes are paralleled by a decrease in NCC phosphorylation and a decrease in the mass of the distal convoluted tubule, exclusive to DCT1. As a result of the dependent nature of OSR1 on SPAK in the DCT, NCC is unable to be activated. Consequently, SPAK(-/-) mice are highly sensitive to dietary salt restriction, displaying prolonged negative sodium balance and hypotension.
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