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 4

WNK body condensate expression is dependent upon blood [K+] and correlates with pNCC amplification during potassium deficiency.

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WNK body condensate expression is dependent upon blood [K+] and correlat...
(A) IF of WNK bodies in WT male mice treated with various potassium maneuvers for 10 days to induce a broad range of blood K+ concentrations. DCTs were identified by NCC costaining. WNK4+ puncta progressively increased in size as [K+] fell and were not visible above a [K+] of 4.0. Scale bar: 10 μm (B) Quantification of WNK body size as a function of blood [K+], fit to a single exponential curve; R2 = 0.9757, P < 0.0001 vs. a horizontal line through the mean of Y values. This demonstrates a WNK body size dependence on [K+]. (C) Cropped and adapted image from Figure 3B integrated with WNK body expression and pNCC amplification. As [K+] falls below 4.0 mmol/L, WT mice amplify NCC phosphorylation more effectively than KS-WNK1–KO mice, correlating with WNK body expression. (D) CLEM of a semithin (~300 nm) DCT section in a hypokalemic WT mouse combining confocal with backscattered-electron scanning electron microscopy (BSE-SEM). WNK bodies were detected with a WNK1 primary and a dual Alexa Fluor 488/5 nm gold particle–conjugated secondary. The image is inverted; thus, areas of low signal intensity represent lower BSE reflectivity. WNK body condensates contained immunogold signal that clustered within membraneless perinuclear cytosolic regions of lower material density. Scale bar: 200 nm.