ArticleJournal of the American Society of Nephrology : JASN2016
Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na⁺-K⁺-2Cl⁻ Cotransporter.
Article in Journal of the American Society of Nephrology : JASN, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 34 citations in OpenAlex.
- Pre-CRRT furosemide and mortality in sepsis-associated AKI: A retrospective cohort study.PloS one · 2026Article
- TNF inhibits NKCC2 phosphorylation by a calcineurin-dependent pathway.American journal of physiology. Renal physiology · 2025Article
- Role of calcineurin in regulating renal potassium (KActa physiologica (Oxford, England) · 2024Review
- Cyclosporin-induced hypertension is associated with the up-regulation of Na+-K+-2Cl- cotransporter (NKCC2).Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2024Article
- Update on NKCC2 regulation in the thick ascending limb (TAL) by membrane trafficking, phosphorylation, and protein-protein interactions.Frontiers in physiology · 2024Review
- A novel mouse model for an inducible gene modification in the renal thick ascending limb.American journal of physiology. Renal physiology · 2023Article
- Calcineurin inhibitors stimulate Kir4.1/Kir5.1 of the distal convoluted tubule to increase NaCl cotransporter.JCI insight · 2023Article
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
- Golgi Alpha1,2-Mannosidase IA Promotes Efficient Endoplasmic Reticulum-Associated Degradation of NKCC2.Cells · 2021Article
- Calcineurin inhibitors: a double-edged sword.American journal of physiology. Renal physiology · 2021Review
- Review
- The Many Faces of Calcineurin Inhibitor Toxicity-What the FK?Advances in chronic kidney disease · 2020Review
- Molecular regulation of NKCC2 in blood pressure control and hypertension.Current opinion in nephrology and hypertension · 2019Review
- Caveolin 1 Promotes Renal Water and Salt Reabsorption.Scientific reports · 2018Article
- Regulation of renal Na-(K)-Cl cotransporters by vasopressin.Pflugers Archiv : European journal of physiology · 2017Review
- Sorting receptor SORLA: cellular mechanisms and implications for disease.Cellular and molecular life sciences : CMLS · 2017Review
- Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms.American journal of physiology. Renal physiology · 2017Article
- AVP dynamically increases paracellular NaPflugers Archiv : European journal of physiology · 2017Review
- Extracellular KThe Journal of physiology · 2016Article
- Corticomedullary difference in the effects of dietary Ca²⁺ on tight junction properties in thick ascending limbs of Henle's loop.Pflugers Archiv : European journal of physiology · 2016Article
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
The furosemide-sensitive Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2) is crucial for NaCl reabsorption in kidney thick ascending limb (TAL) and drives the urine concentrating mechanism. NKCC2 activity is modulated by N-terminal phosphorylation and dephosphorylation. Serine-threonine kinases that activate NKCC2 have been identified, but less is known about phosphatases that deactivate NKCC2. Inhibition of calcineurin phosphatase has been shown to stimulate transport in the TAL and the distal convoluted tubule. Here, we identified NKCC2 as a target of the calcineurin Aβ isoform. Short-term cyclosporine administration in mice augmented the abundance of phospho-NKCC2, and treatment of isolated TAL with cyclosporine increased the chloride affinity and transport activity of NKCC2. Because sorting-related receptor with A-type repeats (SORLA) may affect NKCC2 phosphoregulation, we used SORLA-knockout mice to test whether SORLA is involved in calcineurin-dependent modulation of NKCC2. SORLA-deficient mice showed more calcineurin Aβ in the apical region of TAL cells and less NKCC2 phosphorylation and activity compared with littermate controls. In contrast, overexpression of SORLA in cultured cells reduced the abundance of endogenous calcineurin Aβ. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin Aβ and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin Aβ and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for immunosuppressive therapy using calcineurin inhibitors.
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Registered trials
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.