Journal article
Roles of WNK1 and mTORC2 in aldosterone-independent regulation of potassium secretion in the distal nephron
Kidney international
04/23/2026
DOI: 10.1016/j.kint.2026.03.014
PMID: 42034200
Abstract
Precise regulation of kidney potassium excretion is essential for maintaining plasma potassium concentration within narrow limits in the face of wide variations in intake. Aldosterone has long been considered the key regulator of tubule potassium secretion. However, increasing evidence suggests that it plays a relatively limited role over a wide range of potassium ingestion. Here we investigated the roles of WNK1 kinase and the mTORC2 regulatory complex in potassium secretion in the distal nephron of mice.
We generated knockout (KO) mice where alternatively mTORC2 or the potassium-sensitive kinase, WNK1, were selectively disrupted in the late distal convoluted tubule and early connecting tubule (DCT2/CNT
), an important site of potassium secretion. KO mice were subjected to an acute increase in dietary potassium, after which fluid and electrolyte parameters were measured, and subcellular localization and activity of key ion channels were assessed using immunofluorescence and patch clamp, respectively. Phosphorylation state of mTORC2 targets was determined using Western blot.
In mice lacking mTORC2 in the DCT2/CNT
, urinary potassium excretion failed to increase adequately in response to high potassium intake, while sodium, chloride and net urine output were excessive, resulting in hyperkalemia and fluid volume wasting. Immunofluorescence and patch clamp revealed that active apical membrane sodium channels (αENaC) in DCT2/CN
failed to increase. Furthermore, KO mice lacking WNK1 in the DCT2/CNT
similarly have diminished potassium excretion and diminished mTORC2-dependent phosphorylation of key targets involved in potassium secretion.
These findings strongly support the idea that a WNK1-mTORC2-dependent signaling pathway acts selectively in the DCT2/CNT
to regulate potassium secretion in an aldosterone-independent manner.
Details
- Title: Subtitle
- Roles of WNK1 and mTORC2 in aldosterone-independent regulation of potassium secretion in the distal nephron
- Creators
- Bidisha Saha - University of California, San FranciscoEnzo Takagi - University of California, San FranciscoCheng-Biao Zhang - New York Medical CollegeJohn Demko - University of California, San FranciscoRobert Weber - University of California, San FranciscoKen Kaseda - The University of TokyoJian Xie - University of IowaAnna Manis - University of California, San FranciscoDeise Carla Almeida Leite Dellova - Department of Medicine, Division of Nephrology, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA, USAMads Vaarby Sørensen - Aarhus UniversityChou-Long Huang - University of IowaShigeru Shibata - The University of TokyoWen-Hui Wang - New York Medical CollegeDavid Pearce - University of California, San Francisco
- Resource Type
- Journal article
- Publication Details
- Kidney international
- DOI
- 10.1016/j.kint.2026.03.014
- PMID
- 42034200
- ISSN
- 1523-1755
- eISSN
- 1523-1755
- Publisher
- Elsevier
- Language
- English
- Electronic publication date
- 04/23/2026
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9985157523902771
Metrics
1 Record Views