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Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules
P Richard Grimm1, Richard Coleman1, Eric Delpire2
1Department of Physiology, Maryland Kidney Discovery Center, University of Maryland Medical School, Baltimore, Maryland; and.
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.
Insights
Familial hyperkalemic hypertension (FHHt) involves kidney sodium-chloride cotransporter (NCC) hyperactivity. This study reveals that while NCC is key, aberrant aldosterone-sensitive distal nephron (ASDN) function also drives FHHt, impacting potassium balance.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Familial hyperkalemic hypertension (FHHt) is linked to aberrant activation of with no lysine (WNK) kinases.
- Thiazide diuretics, a treatment for FHHt, suggest hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is the primary cause.
- However, the roles of the aldosterone-sensitive distal nephron (ASDN) and the renal outer medullary potassium (ROMK) channel in FHHt pathogenesis remain unclear.
Purpose of the Study:
- To investigate the specific role of Ste20-related proline-alanine-rich kinase (SPAK), the terminal kinase in the WNK pathway, in FHHt.
- To determine if NCC hyperactivity alone explains hyperkalemia in FHHt or if other nephron segments are involved.
- To elucidate the coupling mechanism between the DCT and ASDN in regulating potassium excretion.
Main Methods:
- Generated mice with kidney-specific expression of constitutively active (CA)-SPAK in the early DCT using a DCT-driven Cre recombinase system.
- Analyzed physiological parameters including blood pressure, serum potassium levels, and urinary electrolyte excretion.
- Assessed NCC phosphorylation, ASDN structure, and expression/localization of epithelial sodium channel (ENaC) and ROMK.
Main Results:
- CA-SPAK mice exhibited thiazide-treatable hypertension and hyperkalemia, with evidence of NCC hyperphosphorylation.
- Thiazide treatment normalized NCC activity and sodium excretion but did not immediately restore urinary potassium excretion.
- CA-SPAK mice showed ASDN remodeling, reduced ENaC and ROMK expression/localization, which gradually improved with DCT NCC blockade.
Conclusions:
- NCC hyperactivity is a critical driver of FHHt, as confirmed by CA-SPAK mouse models.
- Hyperkalemia in FHHt is not solely due to NCC-dependent changes in potassium secretion driving force.
- A DCT-ASDN coupling mechanism is essential for potassium homeostasis and is aberrantly activated in FHHt.
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