TY - JOUR
T1 - Dietary potassium stimulates Ppp1Ca-Ppp1r1a dephosphorylation of kidney NaCl co-transporter and reduces blood pressure
AU - Grimm, Paul Richard
AU - Tatomir, Anamaria
AU - Rosenbaek, Lena L
AU - Kim, Bo Young
AU - Li, Dimin
AU - Delpire, Eric J
AU - Fenton, Robert A
AU - Welling, Paul A
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
KW - Animals
KW - Blood Pressure/physiology
KW - Hypertension/genetics
KW - Kidney/metabolism
KW - Mice
KW - Phosphorylation
KW - Potassium, Dietary/metabolism
KW - Potassium/metabolism
KW - Protein Serine-Threonine Kinases/genetics
KW - Sodium Chloride/metabolism
KW - Solute Carrier Family 12, Member 3/genetics
UR - http://www.scopus.com/inward/record.url?scp=85175741064&partnerID=8YFLogxK
U2 - 10.1172/JCI158498
DO - 10.1172/JCI158498
M3 - Journal article
C2 - 37676724
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 21
M1 - e158498
ER -