Potassium-Switch Signaling Pathway Dictates Acute Blood Pressure Response to Dietary Potassium

Paul A. Welling, Robert Little, Lama Al-Qusairi, Eric Delpire, David H. Ellison, Robert A. Fenton, P. Richard Grimm

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Potassium (K+)-deficient diets, typical of modern processed foods, increase blood pressure (BP) and NaCl sensitivity. A K+-dependent signaling pathway in the kidney distal convoluted tubule, coined the K+switch, that couples extracellular K+sensing to activation of the thiazide-sensitive NaCl cotransporter (NCC) and NaCl retention has been implicated, but causality has not been established. METHODS: To test the hypothesis that small, physiological changes in plasma K+(PK+) are translated to BP through the switch pathway, a genetic approach was used to activate the downstream switch kinase, SPAK (SPS1-related proline/alanine-rich kinase), within the distal convoluted tubule. The CA-SPAK (constitutively active SPS1-related proline/alanine-rich kinase mice) were compared with control mice over a 4-day PK+titration (3.8-5.1 mmol) induced by changes in dietary K+. Arterial BP was monitored using radiotelemetry, and renal function measurements, NCC abundance, phosphorylation, and activity were made. RESULTS: As PK+decreased in control mice, BP progressively increased and became sensitive to dietary NaCl and hydrochlorothiazide, coincident with increased NCC phosphorylation and urinary sodium retention. By contrast, BP in CA-SPAK mice was elevated, resistant to the PK+titration, and sensitive to hydrochlorothiazide and salt at all PK+levels, concomitant with sustained and elevated urinary sodium retention and NCC phosphorylation and activity. Thus, genetically locking the switch on drives NaCl sensitivity and prevents the response of BP to potassium. CONCLUSIONS: Low K+, common in modern ultraprocessed diets, presses the K+-switch pathway to turn on NCC activity, increasing sodium retention, BP, and salt sensitivity.

Original languageEnglish (US)
Pages (from-to)1044-1054
Number of pages11
Issue number5
StatePublished - May 1 2024


  • hydrochlorothiazide
  • hypertension
  • phosphorylation
  • potassium
  • sodium chloride

ASJC Scopus subject areas

  • Internal Medicine


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