Dietary potassium stimulates Ppp1Ca-Ppp1r1a dephosphorylation of kidney NaCl cotransporter and reduces blood pressure
P. Richard Grimm, Anamaria Tatomir, Lena L. Rosenbaek, Bo Young Kim, Dimin Li, Eric J. Delpire, Robert A. Fenton, Paul A. Welling
P. Richard Grimm, Anamaria Tatomir, Lena L. Rosenbaek, Bo Young Kim, Dimin Li, Eric J. Delpire, Robert A. Fenton, Paul A. Welling
View: Text | PDF
Research Article Nephrology

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

Abstract

Consumption of low dietary potassium, common with ultraprocessed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the with no (K) lysine kinase/STE20/SPS1-related proline-alanine–rich protein kinase (WNK/SPAK) pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high-potassium “DASH-like” diets (dietary approaches to stop hypertension) inactivate the cotransporter and whether this decreases BP. A transcriptomics screen identified Ppp1Ca, encoding PP1A, as a potassium-upregulated 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 dephosphorylated NCC directly in a potassium-regulated manner. Prior adaptation to a high-potassium diet was required to maximally dephosphorylate NCC and lower BP in 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 drove 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.

Authors

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

×

Figure 3

Dietary potassium differentially regulates Ppp1Ca and Ppp1r1a genes in the kidney.

Options: View larger image (or click on image) Download as PowerPoint
Dietary potassium differentially regulates Ppp1Ca and Ppp1r1a genes in t...
(A) Targeted protein phosphatase screen comparing all 71 serine/threonine phosphatases and regulatory subunits in the kidney. Heatmap shows the transcript abundance of each protein phosphatase (labeled on the left) relative to control mice (homozygous for WT SPAK, WT/WT) on a control diet. Control (WT/WT) and homozygous CA-SPAK mice (CA/CA) on control (Ctrl) and high-potassium diets (HK) are compared. Green indicates downregulated (Down); red indicates upregulated (Up). n = 7 mice per group. *P < 0.05, by 1-way ANOVA for all groups followed by Tukey’s comparison (genes whose expression significantly changed by at least 20% from WT/WT levels in mice on the control diet are indicated with a single asterisk and were selected for validation). (B) qPCR validation of potassium-dependent regulation of Ppp1Ca and Ppp1R1a. Each dot is a separate mouse. Transcript abundances are shown relative to control mice on the control diet (WT/WT SPAK). Statistical significance was assessed as above. *P < 0.05, statistical differences for diet effect within a genotype; #P < 0.05, statistical difference between CA/– and CA/CA mice on a control diet versus WT/WT mice on a control diet. Data are the mean ± SEM. n >7. (C) Relative transcript abundance versus plasma potassium concentration. Best-fit lines (as determined by F test analysis) are shown. Ppp1Ca and Ppp1r1a lines are fit to abundance = maximum abundance/1 + (K1/2/PK+)n. Ppp3ca is fit to linear.