Show simple item record

dc.contributor.authorGrimm, P.R.
dc.contributor.authorColeman, R.
dc.contributor.authorDelpire, E.
dc.date.accessioned2019-10-08T19:43:53Z
dc.date.available2019-10-08T19:43:53Z
dc.date.issued2017
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85025094879&doi=10.1681%2fASN.2016090948&partnerID=40&md5=9ad558349af8804a76d1d302a685ced3
dc.identifier.urihttp://hdl.handle.net/10713/11126
dc.description.abstractAberrant 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 potassiumexcretory renal outermedullary 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 earlyDCT 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, concurrentwith the restoration of urinary potassiumexcretion. 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.en_US
dc.description.sponsorshipFunding for this project was provided National Institutes of Health Grants DK63049, DK54231, and DK093501.en_US
dc.description.urihttps://doi.org/10.1681/ASN.2016090948en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society of Nephrologyen_US
dc.relation.ispartofJournal of the American Society of Nephrology
dc.subject.meshHydrochlorothiazide--pharmacologyen_US
dc.subject.meshKidney Tubules, Distal--pathologyen_US
dc.subject.meshProtein-Serine-Threonine Kinases--metabolismen_US
dc.subject.meshPseudohypoaldosteronismen_US
dc.subject.meshSodium Chloride Symporter Inhibitors--pharmacologyen_US
dc.subject.meshSolute Carrier Family 12, Member 3--metabolismen_US
dc.titleConstitutively active SPAK causes hyperkalemia by activating NCC and remodeling distal tubulesen_US
dc.typeArticleen_US
dc.identifier.doi10.1681/ASN.2016090948
dc.identifier.pmid28442491


This item appears in the following Collection(s)

Show simple item record