Thanks so much Pablo!

Congrats to Cary Boyd-Shiwarski @caryboyd.bsky.social , who expertly saw this through as corresponding author, lab members & alums; and to our collaborators including @simoncwatkins.bsky.social & the Kashlan, Rodan, Huang, and Stocker labs 🎉🥳🍾 /12

More generally, this work extends beyond functional studies in cells to support the relevance of biomolecular #condensates in mammalian #physiology, while hinting @ intriguing connections between condensates & public health. 11/

This is consistent w/ a population-scale metanalysis suggesting that a [K+] <4.0mmol/L is associated w/ increased CV mortality. Perhaps “destressing” the kidney via blood K+ titration could be leveraged to optimize health. Highlighted by Pitt SoM here 10/
www.medschool.pitt.edu/news/kidney-...

In human kidneys, WNK bodies accumulated as [K+] progressively fell below 4.0mmol/L. This suggests that the human DCT hyperactivates 🧂 reabsorption even when K+ is 3.5-4.0. Thus, a K+ in the low-normal range may not be ideal for CV 🫀 health, as it may predispose to salt-sensitive HTN 9/

Compared to males, K+ restricted female mice were more dependent on WNK bodies for optimal electrolyte balance, indicating that WNK body condensates contribute to nephron sexual dimorphism. 8/

Using KO and transgenic mouse models, we show that KS-WNK1 activates NCC via WNK bodies during dietary K+ deficiency and inhibits NCC during K+ excess. KS-WNK1 therefore functions as a signal amplifier 📶 that expands the dynamic range of DCT reactivity to [K+] 7/

…This is because during hypokalemia, the DCT WNK signaling pathway forms specialized condensates termed WNK bodies. These assemblies require KS-WNK1, a truncated DCT-specific WNK1 isoform. KS-WNK1 encodes the large IDR that drives WNK1 phase behavior; basically, it’s a disordered scaffold 6/

In 2022, we reported that WNKs activate ion transport via IDR-mediated phase separation: www.cell.com/cell/fulltex... . WNK condensates emerged in unicellular species to control cell volume, but we hypothesized that they were repurposed by evolution to regulate kidney tubule ion transport... 5/

Some background: The kidney regulates K+ homeostasis. The distal convoluted tubule (DCT) controls Na+ dependent kaliuresis by amplifying small changes in blood K+ into large effects on 🧂 reabsorption via the NaCl cotransporter NCC. WNK kinases mediate this but the details have been unclear 4/

The paper was also paired with a lovely editorial penned by two masters of distal nephron physiology, Gerardo Gamba and David Ellison (thank you!) 🙏🏽: 3/
www.jci.org/articles/vie...

This paper integrates years of research that initially started in the kidney, dove into fundamental condensate biology in cells, and circled back to mouse models & a translational analysis in humans. Read the full article here www.jci.org/articles/vie... 2/