SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na(+)-K(+)-Cl(-) cotransporter 2.
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.
Reiche
Juliane
J
Max Delbrück Center for Molecular Medicine, Charité, Universitätsmedizin, 13125 Berlin, Germany.
Theilig
Franziska
F
Rafiqi
Fatema H
FH
Carlo
Anne-Sophie
AS
Militz
Daniel
D
Mutig
Kerim
K
Todiras
Mihail
M
Christensen
Erik Ilsø
EI
Ellison
David H
DH
Bader
Michael
M
Nykjaer
Anders
A
Bachmann
Sebastian
S
Alessi
Dario
D
Willnow
Thomas E
TE
D000818:Animals; D004703:Endocrine System / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006706:Homeostasis; D007150:Immunohistochemistry; D007477:Ions / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011973:Receptors, LDL / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D012492:Salts / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1; D013347:Subcellular Fractions / Q000378:metabolism; D014020:Tissue Extracts
D053503:Epithelial Sodium Channels; D007477:Ions; C510693:Kcnj1 protein, mouse; D026901:Membrane Transport Proteins; D024661:Potassium Channels, Inwardly Rectifying; D011973:Receptors, LDL; D012492:Salts; C578715:Slc12a1 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; C491168:Sorl1 protein, mouse; D014020:Tissue Extracts; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases
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