{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:35:48Z","timestamp":1791275748278,"version":"4.1.0"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">Stk39<\/jats:italic>\n                    gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine\u2013rich 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.\n                  <\/jats:p>","DOI":"10.1681\/asn.2016090948","type":"journal-article","created":{"date-parts":[[2017,4,25]],"date-time":"2017-04-25T20:55:44Z","timestamp":1493153744000},"page":"2597-2606","source":"Crossref","is-referenced-by-count":139,"title":["Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules"],"prefix":"10.1681","volume":"28","author":[{"given":"P. Richard","family":"Grimm","sequence":"first","affiliation":[{"name":"Department of Physiology, Maryland Kidney Discovery Center, University of Maryland Medical School, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Physiology, Maryland Kidney Discovery Center, University of Maryland Medical School, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Delpire","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vanderbilt University Medical School, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Welling","sequence":"additional","affiliation":[{"name":"Department of Physiology, Maryland Kidney Discovery Center, University of Maryland Medical School, Baltimore, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,4,25]]},"reference":[{"key":"B1-20230819","doi-asserted-by":"crossref","first-page":"7929","DOI":"10.1073\/pnas.1200947109","article-title":"Activation of the renal Na+: Cl\u2212 cotransporter by angiotensin II is a WNK4-dependent process.","volume":"109","author":"Casta\u00f1eda-Bueno","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B2-20230819","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1172\/JCI65460","article-title":"The absence of intrarenal ACE protects against hypertension.","volume":"123","author":"Gonzalez-Villalobos","year":"2013","journal-title":"J Clin Invest"},{"key":"B3-20230819","doi-asserted-by":"crossref","first-page":"e00107","DOI":"10.1042\/BSR20140047","article-title":"WNK4 is the major WNK positively regulating NCC in the mouse kidney.","volume":"34","author":"Takahashi","year":"2014","journal-title":"Biosci 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