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 identified 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 the 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 (NKCC) 2, 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 mis-sorting of SPAK. Our data suggests 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.