SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na+-K+-Cl- cotransporter 2

Juliane Reiche, Franziska Theilig, Fatema H. Rafiqi, Anne Sophie Carlo, Daniel Militz, Kerim Mutig, Mihail Todiras, Erik Ilsø Christensen, David Ellison, Michael Bader, Anders Nykjaer, Sebastian Bachmann, Dario Alessi, Thomas E. Willnow

Research output: Contribution to journalArticle

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Abstract

Proper control of NaCl excretion in the kidney is central to bodily functions, yet many mechanisms that regulate reabsorption of sodium and chloride in the kidney remain incompletely understood. Here, we identify an important role played by the intracellular sorting receptor SORLA (sorting protein-related receptor with A-type repeats) in functional activation of renal ion transporters. We demonstrate that SORLA is expressed in epithelial cells of the thick ascending limb (TAL) of Henle's loop and that lack of receptor expression in this cell type in SORLA-deficient mice results in an inability to properly reabsorb sodium and chloride during osmotic stress. The underlying cellular defect was correlated with an inability of the TAL to phosphorylate Na +-K+-Cl- cotransporter 2 (NKCC2), the major sodium transporter in the distal nephron. SORLA functionally interacts with Ste-20-related proline-alanine-rich kinase (SPAK), an activator of NKCC2, and receptor deficiency is associated with missorting of SPAK. Our data suggest a novel regulatory pathway whereby intracellular trafficking of SPAK by the sorting receptor SORLA is crucial for proper NKCC2 activation and for maintenance of renal ion balance.

Original languageEnglish (US)
Pages (from-to)3027-3037
Number of pages11
JournalMolecular and Cellular Biology
Volume30
Issue number12
DOIs
StatePublished - Jun 2010

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Sodium-Potassium-Chloride Symporters
Proline
Alanine
Phosphotransferases
Kidney
Sodium Chloride
Ions
Loop of Henle
Nephrons
Osmotic Pressure
Protein Transport
Extremities
Epithelial Cells
Sodium
Maintenance

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Reiche, J., Theilig, F., Rafiqi, F. H., Carlo, A. S., Militz, D., Mutig, K., ... Willnow, T. E. (2010). SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na+-K+-Cl- cotransporter 2. Molecular and Cellular Biology, 30(12), 3027-3037. https://doi.org/10.1128/MCB.01560-09

SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na+-K+-Cl- cotransporter 2. / Reiche, Juliane; Theilig, Franziska; Rafiqi, Fatema H.; Carlo, Anne Sophie; Militz, Daniel; Mutig, Kerim; Todiras, Mihail; Christensen, Erik Ilsø; Ellison, David; Bader, Michael; Nykjaer, Anders; Bachmann, Sebastian; Alessi, Dario; Willnow, Thomas E.

In: Molecular and Cellular Biology, Vol. 30, No. 12, 06.2010, p. 3027-3037.

Research output: Contribution to journalArticle

Reiche, J, Theilig, F, Rafiqi, FH, Carlo, AS, Militz, D, Mutig, K, Todiras, M, Christensen, EI, Ellison, D, Bader, M, Nykjaer, A, Bachmann, S, Alessi, D & Willnow, TE 2010, 'SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na+-K+-Cl- cotransporter 2', Molecular and Cellular Biology, vol. 30, no. 12, pp. 3027-3037. https://doi.org/10.1128/MCB.01560-09
Reiche, Juliane ; Theilig, Franziska ; Rafiqi, Fatema H. ; Carlo, Anne Sophie ; Militz, Daniel ; Mutig, Kerim ; Todiras, Mihail ; Christensen, Erik Ilsø ; Ellison, David ; Bader, Michael ; Nykjaer, Anders ; Bachmann, Sebastian ; Alessi, Dario ; Willnow, Thomas E. / SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na+-K+-Cl- cotransporter 2. In: Molecular and Cellular Biology. 2010 ; Vol. 30, No. 12. pp. 3027-3037.
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