Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates
Cary R. Boyd-Shiwarski, … , Ossama B. Kashlan, Arohan R. Subramanya
Cary R. Boyd-Shiwarski, … , Ossama B. Kashlan, Arohan R. Subramanya
Published June 10, 2025
Citation Information: J Clin Invest. 2025;135(15):e188792. https://doi.org/10.1172/JCI188792.
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Research Article Cell biology Nephrology

Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates

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 amplified kidney tubule reactivity to blood [K+], in part via WNK bodies. In genetically modified mice, targeted condensate disruption trapped the WNK pathway, causing renal salt wasting that was more pronounced in females. In humans, WNK bodies accumulated as plasma potassium fell below 4.0 mmol/L, suggesting that the human DCT experiences the stress of potassium deficiency, even when [K+] is in the low-to-normal range. These data identify WNK bodies as kinase signal amplifiers that mediate tubular [K+] responsiveness, nephron sexual dimorphism, and BP salt sensitivity. Our results illustrate how biomolecular condensate specialization can optimize a mammalian physiologic stress response that impacts human health.

Authors

Cary R. Boyd-Shiwarski, Rebecca T. Beacham, Jared A. Lashway, Katherine E. Querry, Shawn E. Griffiths, Daniel J. Shiwarski, Sophia A. Knoell, Nga H. Nguyen, Lubika J. Nkashama, Melissa N. Valladares, Anagha Bandaru, Allison L. Marciszyn, Jonathan Franks, Mara Sullivan, Simon C. Watkins, Aylin R. Rodan, Chou-Long Huang, Sean D. Stocker, Ossama B. Kashlan, Arohan R. Subramanya

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Figure 10

WNK bodies are necessary for KS-WNK1 to amplify NCC phosphorylation during hypokalemia.

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WNK bodies are necessary for KS-WNK1 to amplify NCC phosphorylation duri...
(A) WT and 5Q mice were fed control or low K+ diet for 10 days, and kidney cortex homogenates were probed for tNCC, pNCC, tSPAK, and pSPAK/pOSR1. Brackets indicate the band analyzed. (B–E) Graphical representation of immunoblots in A. (B) tNCC abundance. (C) pNCC abundance. (D) tSPAK abundance. (E) pSPAK/pOSR1 abundance. K+-restricted 5Q mice had significantly increased pSPAK/pOSR1 and reduced tNCC and pNCC expression, indicating that signaling to NCC was uncoupled. n = 6 mice per genotype, sex, and diet. Two-way ANOVA with Šídák’s post test was applied, *P < 0.05, **P < 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. (F) Model of WNK-SPAK/OSR1-NCC signaling in WT, KS-WNK1–KO, and 5Q mice. KS-WNK1 normally facilitates WNK body condensate formation and NCC activation via the WNK-SPAK/OSR1 pathway. In K+-restricted KS-WNK1–KO mice, WNK bodies are largely absent and remaining complexes are mislocalized, resulting in low SPAK/OSR1 and NCC activity. In the K+-restricted 5Q mouse, WNK-pSPAK/pOSR1 becomes trapped in perinuclear aggregates, preventing pSPAK/pOSR1 expression at the DCT apical membrane, causing a reduction in NCC activity. See also Supplemental Table 4.