Abstract
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 mouse Stk39 gene, 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.
Highlights
With no lysine (WNK) kinase signaling cascades form a molecular switch that adjusts the aldosterone response of the kidney to either retain sodium or excrete potassium depending on physiologic need
We found that an unexpected distal tubule (DCT-aldosterone-sensitive distal nephron (ASDN)) coupling process inversely links NCC activity to urinary potassium excretion
Ste20-related proline-alanine–rich kinase (SPAK) expression in the DCT1 is accompanied by an ASDN remodeling program characterized by ASDN dystrophy and inhibition of ENaC and ROMK
Summary
The finding of Lalioti et al.[10] that genetic ablation of NCC abolishes hypertension and hyperkalemia in WNK4-FHHt. Propose that NCC-dependent changes in sodium delivery These findings reinforce the importance of the early distal tu- shape longer-term “remodeling” of the potassium secretory bule and phosphoactivation of NCC45 in the control of salt machinery in the ASDN, reminiscent of the way that sodium modulates DCT structure and transport.[49] It will be interesting to learn if CNT-specific ENaC KO mice have dystrophic CNT as predicted if sodium is the sole mediator of the remodeling process. This study reveals that WNK-SPAK signaling in the DCT1 is sufficient to drive the switch mechanism to activate salt transport from the DCTand suppress potassium secretion from the ASDN through a surprising transtubule coupling mechanism
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