Kidney-Specific WNK1 Amplifies NCC Responsiveness to Potassium Imbalance
Boyd-Shiwarski, C. R.; Beacham, R. T.; Griffiths, S. E.; Shiwarski, D. J.; Knoell, S. A.; Nkashama, L. J.; Querry, K. E.; Marciszyn, A. L.; Huang, C.-L.; Stocker, S. D.; Subramanya, A. R.
Show abstract
To maintain potassium homeostasis, the kidneys distal convoluted tubule (DCT) converts small changes in blood [K+] into robust effects on salt reabsorption. This process requires NaCl cotransporter (NCC) activation by 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 the dynamic range of NCC activity in response to potassium imbalance, in part via WNK bodies. Targeted condensate disruption traps the WNK pathway, causing renal salt-wasting that is more pronounced in females. In humans, WNK bodies accumulate as plasma potassium falls below 4.0mmol/L, suggesting avid condensate-mediated salt reabsorption even when [K+] is low-normal. These data identify WNK bodies as signal amplifiers that mediate tubular potassium responsiveness, nephron sexual dimorphism, and blood pressure salt-sensitivity. Our results illustrate how condensate specialization can optimize a mammalian physiologic stress response that impacts human health.
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