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The cloning of the related sodium chloride (NCC) and sodium potassium 2 chloride (NKCC) co-transporters in the early 1990s ushered in a new era for understanding the mechanisms of renal salt handling.1 Recent research has focused on the phosphoregulation of NCC and the two NKCC co-transporters: NKCC1, which is widely expressed, and NKCC2, which is renal specific. Two closely related kinases, STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1), seem to play a key role in NCC, NKCC1, and NKCC2 phosphorylation. All three co-transporters are phosphorylated by SPAK and OSR1 on N-terminal cytoplasmic serines and threonines that are conserved among NCC, NKCC1, and NKCC2, and phosphorylation of these residues results in co-transporter activation.2–5The importance of these phosphorylation events for NCC activity was first demonstrated in Xenopus oocytes, in which mutation of these residues to nonphosphorylatable alanines reduced baseline NCC activity as well as stimulation of NCC by intracellular chloride depletion.6 Similar results were then observed in mammalian cells by Richardson et al. ,7 who also showed that, like NCC, SPAK and OSR1 were activated by low intracellular chloride, and mutation of the SPAK/OSR1-binding site of NCC abolished NCC phosphorylation. These results suggest that specific stimuli activate SPAK and OSR1, which in turn activate NCC by phosphorylating N-terminal threonines and serines.The link between SPAK and NCC is strengthened by the report of Yang et al. 8 in this issue of JASN . The authors generated SPAK null mice to demonstrate decreased levels …

An Emerging Role for SPAK in NCC, NKCC, and Blood Pressure Regulation