Kidney-specific WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates
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
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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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 3

KS-WNK1 amplifies the inverse relationship between NCC phosphorylation and blood [K+].

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KS-WNK1 amplifies the inverse relationship between NCC phosphorylation a...
Total and phosphorylated NCC protein abundance in KS-WNK1–KO (red) versus WT (blue) mice, plotted as a function of blood [K+]. (A–C) tNCC, pNCC, and pNCC /tNCC ratio, fit to single exponential curves. R2 measures are presented in table format alongside the graphs. For all graphs, the single exponential function adequately fit the WT data at [K+] <4.0 but overestimated data points at [K+] >6.0 (filled blue circles). (D–F) Normalized tNCC, pNCC, and pNCC/tNCC densitometry in A–C was log transformed and analyzed by linear regression. In all cases, WT data were best fit by a segmented linear regression regime, with X0 breakpoints (dotted line) around 5.6 mmol/L. Slopes of the 2 linear components are presented in table format alongside the corresponding graphs. For KO mice, slopes 1 (X < X0) and 2 (X > X0) did not differ as the log-transformed data were best fit by simple linear regression. P values represent slope comparisons between WT and KO data; since slope 1 comparisons did not reach significance, Y-intercept comparisons with P values are shown. See also Supplemental Figure 5 for results disaggregated by sex and residual plots.