Dietary potassium stimulates Ppp1Ca-Ppp1r1a dephosphorylation of kidney NaCl co-transporter and reduces blood pressure

Paul Richard Grimm, Anamaria Tatomir, Lena L Rosenbaek, Bo Young Kim, Dimin Li, Eric J Delpire, Robert A Fenton, Paul A Welling

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Consumption of low dietary potassium, common with ultra-processed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the WNK-SPAK kinase pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high potassium "DASH-like" diets inactivate the cotransporter and whether this decreases BP. A transcriptomic screen identified Ppp1C⍺, encoding PP1A, as a potassium up-regulated gene, and its negative regulator, Ppp1r1a, as a potassium-suppressed gene in the kidney. PP1A directly binds to and dephosphorylates NCC when extracellular potassium is elevated. Using mice genetically engineered to constitutively activate the NCC-regulatory kinase SPAK and thereby eliminate the effects of the WNK-SPAK kinase cascade, we confirmed that PP1A dephosphorylates NCC directly in a potassium-regulated manner. Prior adaptation to a high potassium diet was required to maximally dephosphorylate NCC and lower BP in the constitutively active SPAK mice, and this was associated with potassium-dependent suppression of Ppp1r1a, and dephosphorylation of its cognate protein, Inhibitory Subunit 1 (I1). In conclusion, potassium-dependent activation of PP1A and inhibition of I1 drives NCC dephosphorylation, providing a mechanism to explain how high dietary K+ lowers BP. Shifting signaling of PP1A in favor of activation of WNK-SPAK may provide an improved therapeutic approach for treating salt-sensitive hypertension.

Original languageEnglish
Article numbere158498
JournalJournal of Clinical Investigation
Number of pages17
Publication statusPublished - Nov 2023


  • Animals
  • Blood Pressure/physiology
  • Hypertension/genetics
  • Kidney/metabolism
  • Mice
  • Phosphorylation
  • Potassium, Dietary/metabolism
  • Potassium/metabolism
  • Protein Serine-Threonine Kinases/genetics
  • Sodium Chloride/metabolism
  • Solute Carrier Family 12, Member 3/genetics


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