Intracellular chloride: A regulator of transepithelial transport in the distal nephron

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations


Purpose of reviewThis 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 findingsLow 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 (WNK)-SPAK/OSR1 (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.SummaryChloride sensing by WNK kinase provides a mechanism to allow coupling of extracellular potassium with NCC phosphorylation and activity to maintain potassium homeostasis.

Original languageEnglish (US)
Pages (from-to)360-367
Number of pages8
JournalCurrent opinion in nephrology and hypertension
Issue number4
StatePublished - Jul 1 2019
Externally publishedYes


  • hyperkalemia
  • hypertension
  • hypokalemia
  • ion transport

ASJC Scopus subject areas

  • Internal Medicine
  • Nephrology


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