Journal article
Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates
The Journal of clinical investigation, Vol.135(15), e188792
08/01/2025
DOI: 10.1172/JCI188792
PMCID: PMC12321387
PMID: 40493421
Abstract
To maintain potassium homeostasis, the kidney's distal convoluted tubule (DCT) evolved to convert small changes in blood [K+] into robust effects on salt reabsorption. This process requires NaCl cotransporter (NCC) activation by the With-No-Lysine (WNK) kinases. During hypokalemia, the Kidney-Specific WNK1 isoform (KS-WNK1) scaffolds the DCT-expressed WNK signaling pathway within biomolecular condensates of unknown function termed WNK bodies. Here, we show that KS-WNK1 amplifies kidney tubule reactivity to blood [K+], in part via WNK bodies. Genetically modified mice with targeted condensate disruption trap the WNK pathway, causing renal salt wasting that is more pronounced in females. In humans, WNK bodies accumulate as plasma potassium falls below 4.0 mmol/L, suggesting that the human DCT experiences the stress of potassium deficiency even when [K+] is in the low-normal range. These data identify WNK bodies as kinase signal amplifiers that mediate tubular [K+] responsiveness, nephron sexual dimorphism, and blood pressure salt-sensitivity. Our results illustrate how biomolecular condensate specialization can optimize a mammalian physiologic stress response that impacts human health.
Details
- Title: Subtitle
- Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates
- Creators
- Cary R Boyd-Shiwarski - University of PittsburghRebecca T Beacham - University of PittsburghJared A Lashway - University of PittsburghKatherine E Querry - University of PittsburghShawn E Griffiths - University of PittsburghDaniel J Shiwarski - University of PittsburghSophia A Knoell - University of PittsburghNga H Nguyen - University of PittsburghLubika J Nkashama - University of PittsburghMelissa N Valladares - University of PittsburghAnagha Bandaru - University of PittsburghAllison L Marciszyn - University of PittsburghJonathan Franks - University of PittsburghMara Sullivan - University of PittsburghSimon C Watkins - University of PittsburghAylin R Rodan - University of UtahChou-Long Huang - University of IowaSean D Stocker - University of PittsburghOssama B Kashlan - University of PittsburghArohan R Subramanya - University of Pittsburgh School of Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.135(15), e188792
- DOI
- 10.1172/JCI188792
- PMID
- 40493421
- PMCID
- PMC12321387
- NLM abbreviation
- J Clin Invest
- ISSN
- 1558-8238
- eISSN
- 1558-8238
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- NIH: K08DK118211, R03DK138215, R00HL155777, R01DK098145, R01DK119252, R01DK110358, R01HL145875, R01HL152680, R01DK111542, R01DK125439, S10OD021627, S10OD028596, P30DK79307, U54DK137329, S10OD036205
We thank Tom Kleyman for helpful discussions. This work was sup-ported by NIH grants K08DK118211 (to CRBS) ; R03DK138215 (to CRBS) ; R00HL155777 (to DJS) ; R01DK098145 (to ARS and ARR) ; R01DK119252 (to ARS) ; R01DK110358 (to ARR) ; R01HL145875 (to SDS) ; R01HL152680 (to SDS) ; R01DK111542 (to CLH) ; R01DK125439 (to OBK) ; S10OD021627, S10OD028596, P30DK79307, and U54DK137329 (Pittsburgh Center for Kidney Research) , S10OD036205 (to SCW) ; and a Carl W. Gottschalk Research Scholar of KidneyCure Award (to CRBS) . This content is solely the responsibility of authors and does not necessarily repre-sent the views of the US Department of Veterans Affairs.
- Language
- English
- Electronic publication date
- 06/10/2025
- Date published
- 08/01/2025
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984829890202771
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