PMID- 28442491 OWN - NLM STAT- MEDLINE DCOM- 20171003 LR - 20220125 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 28 IP - 9 DP - 2017 Sep TI - Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules. PG - 2597-2606 LID - 10.1681/ASN.2016090948 [doi] AB - 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. CI - Copyright (c) 2017 by the American Society of Nephrology. FAU - Grimm, P Richard AU - Grimm PR AD - Department of Physiology, Maryland Kidney Discovery Center, University of Maryland Medical School, Baltimore, Maryland; and. FAU - Coleman, Richard AU - Coleman R AD - Department of Physiology, Maryland Kidney Discovery Center, University of Maryland Medical School, Baltimore, Maryland; and. FAU - Delpire, Eric AU - Delpire E AD - Department of Anesthesiology, Vanderbilt University Medical School, Nashville, Tennessee. FAU - Welling, Paul A AU - Welling PA AD - Department of Physiology, Maryland Kidney Discovery Center, University of Maryland Medical School, Baltimore, Maryland; and pwelling@som.umaryland.edu. LA - eng GR - R01 DK054231/DK/NIDDK NIH HHS/United States GR - R01 DK063049/DK/NIDDK NIH HHS/United States GR - R01 DK093501/DK/NIDDK NIH HHS/United States GR - R01 DK110375/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20170425 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (Epithelial Sodium Channels) RN - 0 (Kcnj1 protein, mouse) RN - 0 (Potassium Channels, Inwardly Rectifying) RN - 0 (Sodium Chloride Symporter Inhibitors) RN - 0 (Solute Carrier Family 12, Member 3) RN - 0J48LPH2TH (Hydrochlorothiazide) RN - 4964P6T9RB (Aldosterone) RN - EC 2.7.1.- (Stk39 protein, mouse) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - RWP5GA015D (Potassium) SB - IM CIN - J Am Soc Nephrol. 2017 Sep;28(9):2555-2557. PMID: 28705920 MH - Aldosterone/metabolism MH - Animals MH - Blood Pressure/drug effects MH - Epithelial Sodium Channels/metabolism MH - Hydrochlorothiazide/*pharmacology/therapeutic use MH - Kidney Tubules, Distal/metabolism/*pathology MH - Mice MH - Natriuresis/drug effects MH - Phosphorylation MH - Potassium/urine MH - Potassium Channels, Inwardly Rectifying/metabolism MH - Protein Serine-Threonine Kinases/genetics/*metabolism MH - Pseudohypoaldosteronism/drug therapy/genetics/*metabolism/urine MH - Signal Transduction MH - Sodium Chloride Symporter Inhibitors/*pharmacology/therapeutic use MH - Solute Carrier Family 12, Member 3/*metabolism PMC - PMC5576927 OTO - NOTNLM OT - FHHt OT - NCC OT - Na Reabsorption OT - Parvalbumin-Cre OT - Ste20 kinase EDAT- 2017/04/27 06:00 MHDA- 2017/10/04 06:00 PMCR- 2018/09/01 CRDT- 2017/04/27 06:00 PHST- 2016/09/06 00:00 [received] PHST- 2017/02/27 00:00 [accepted] PHST- 2017/04/27 06:00 [pubmed] PHST- 2017/10/04 06:00 [medline] PHST- 2017/04/27 06:00 [entrez] PHST- 2018/09/01 00:00 [pmc-release] AID - ASN.2016090948 [pii] AID - 2016090948 [pii] AID - 10.1681/ASN.2016090948 [doi] PST - ppublish SO - J Am Soc Nephrol. 2017 Sep;28(9):2597-2606. doi: 10.1681/ASN.2016090948. Epub 2017 Apr 25.