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WNK [with no lysine (K)] kinases regulate renal epithelial ion transport to maintain homeostasis of electrolyte concentrations, extracellular volume, and blood pressure. The SLC12 cation-chloride cotransporters, including the sodium-potassium-2-chloride (NKCC) and sodium chloride cotransporters (NCC), are targets of WNK regulation via the intermediary kinases SPAK (Ste20-related proline/alanine-rich kinase) and OSR1 (oxidative stress response). The pathway is activated by low dietary potassium intake, resulting in increased phosphorylation and activity of NCC. Chloride regulates WNK kinases in vitro by binding to the active site and inhibiting autophosphorylation and has been proposed to modulate WNK activity in the distal convoluted tubule in response to low dietary potassium. WNK-SPAK/OSR1 regulation of NKCC-dependent ion transport is evolutionarily ancient, and it occurs in the Drosophila Malpighian (renal) tubule. Here, we review recent studies from the Drosophila tubule demonstrating cooperative roles for chloride and the scaffold protein Mo25 (mouse protein-25, also known as calcium-binding protein-39) in the regulation of WNK-SPAK/OSR1 signaling in a transporting renal epithelium. Insights gained from this genetically manipulable and physiologically accessible epithelium shed light on molecular mechanisms of regulation of the WNK-SPAK/OSR1 pathway, which is important in human health and disease.

WNK-SPAK/OSR1 signaling: lessons learned from an insect renal epithelium