Intracellular chloride: a regulator of transepithelial transport in the distal nephron.

PURPOSE OF REVIEW:This review focuses on the role of intracellular chloride in regulating transepithelial ion transport in the distal convoluted tubule (DCT) in response to perturbations in plasma potassium homeostasis. RECENT FINDINGS:Low dietary potassium increases the phosphorylation and activity of the sodium chloride cotransporter (NCC) in the DCT, and vice versa, affecting sodium-dependent potassium secretion in the downstream aldosterone-sensitive distal nephron. In cells, NCC phosphorylation is increased by lowering of intracellular chloride, via activation of the chloride-sensitive with no lysine (Ste20-related proline/alanine-rich kinase/oxidative stress response) kinase cascade. In-vivo studies have demonstrated pathway activation in the kidney in response to low dietary potassium. A possible mechanism is lowering of DCT intracellular chloride in response to low potassium because of parallel basolateral potassium and chloride channels. Recent studies support a role for these channels in the response of NCC to varying potassium. Studies examining chloride-insensitive WNK mutants, in the Drosophila renal tubule and in the mouse, lend further support to a role for chloride in regulating WNK activity and transepithelial ion transport. Caveats, alternatives, and future directions are also discussed. SUMMARY:Chloride sensing by WNK kinase provides a mechanism to allow coupling of extracellular potassium with NCC phosphorylation and activity to maintain potassium homeostasis.

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