Journal of the American Society of Nephrology : JASNApr 27, 2017

Constantly Active SPAK Protein May Cause High Blood Potassium by Increasing Salt Transport and Changing Kidney Tubules

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

CA-SPAK mice displayed thiazide-treatable hypertension and hyperkalemia.

Aberrant activation of WNK kinases is linked to familial hyperkalemic hypertension (FHHt).
Constitutively active SPAK results in hyperphosphorylation of the sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT).
Thiazide treatment reduces NCC activity and restores sodium excretion but does not immediately correct potassium excretion in CA-SPAK mice.
Remodeling of the aldosterone-sensitive distal nephron (ASDN) occurs with reduced connecting tubule mass and decreased expression of sodium channels.
NCC hyperactivity contributes to FHHt, but the relationship between NCC activity and potassium secretion is complex, involving DCT-ASDN interactions.

Simplified

Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mousegene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK). Renal expression of the constitutively active (CA)-SPAK mutant was specifically targeted to the early DCT using a DCT-driven Cre recombinase. CA-SPAK mice displayed thiazide-treatable hypertension and hyperkalemia, concurrent with NCC hyperphosphorylation. However, thiazide-mediated inhibition of NCC and consequent restoration of sodium excretion did not immediately restore urinary potassium excretion in CA-SPAK mice. Notably, CA-SPAK mice exhibited ASDN remodeling, involving a reduction in connecting tubule mass and attenuation of epithelial sodium channel (ENaC) and ROMK expression and apical localization. Blocking hyperactive NCC in the DCT gradually restored ASDN structure and ENaC and ROMK expression, concurrent with the restoration of urinary potassium excretion. These findings verify that NCC hyperactivity underlies FHHt but also reveal that NCC-dependent changes in the driving force for potassium secretion are not sufficient to explain hyperkalemia. Instead, a DCT-ASDN coupling process controls potassium balance in health and becomes aberrantly activated in FHHt. Stk39

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Constantly Active SPAK Protein May Cause High Blood Potassium by Increasing Salt Transport and Changing Kidney Tubules

Abstract

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