| Title: | Piezo1 dictates K+ homeostasis through coordinated regulation of the ubiquitin ligase Kelch-like 3 in RBCs and the kidney |
| Journal: | Proceedings of the National Academy of Sciences of the United States of America |
| Published: | 14 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41533447/ |
| DOI: | https://doi.org/10.1073/pnas.2513222123 |
Publication 18530
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
The maintenance of potassium (K+) balance is a fundamental biological process involving multiple tissues. However, the roles of intertissue crosstalk in K+ homeostasis remain poorly understood. Here, we demonstrate that the mechanosensor Piezo1 dictates extracellular K+ homeostasis by orchestrating the ubiquitin ligase Kelch-like 3 (KLHL3) activity in red blood cells (RBCs; erythrocytes) and the kidney. Genetic variants within KLHL3 with expression quantitative trait locus effects are associated with altered RBC parameters, and CRISPR-generated KLHL3 knock-in (KLHL3-KI) mice carrying a nonphosphorylatable Ala substitution at its activation site (Ser433) reveal that KLHL3 regulates erythrocyte volume by modulating with-no-lysine 1 (WNK1). In wild-type, but not in KLHL3-KI, erythrocytes, Piezo1 activates KLHL3 through Ser433 dephosphorylation, reducing WNK1 abundance and intracellular K+ content-a physiologically adaptive response to hypo-osmotic stress. KLHL3-KI mice exhibit hyperkalemia and reduced fractional K+ excretion, accompanied by elevated WNK levels and reduced renal outer medullary K+ (ROMK) abundance in collecting ducts of the kidney. Single-cell transcriptomics confirm coexpression of Piezo1 and KLHL3 in these segments, where Piezo1 regulates WNK abundance through KLHL3-Ser433 dephosphorylation. In human genetic studies of 200,367 UK Biobank participants, the PIEZO1 missense variant rs563555492 (p.L2277M) is independently associated with lower urinary K+. Piezo1-mediated WNK1 regulation is abolished in human kidney cells expressing Piezo1L2277M. Causal role of Piezo1 in regulating K+ excretion and ROMK was confirmed in vivo. These findings identify Piezo1-KLHL3 interaction as a key intertissue signaling mechanism between erythrocytes and the kidney that governs K+ homeostasis, and suggest this pathway as a therapeutic target for dyskalemia.</p>
13 Keywords
- Adaptor Proteins, Signal Transducing
- Animals
- Erythrocytes
- Homeostasis
- Humans
- Ion Channels
- Kidney
- Male
- Mice
- Microfilament Proteins
- Potassium
- Ubiquitin-Protein Ligases
- WNK Lysine-Deficient Protein Kinase 1
8 Authors
- Kenichi Ishizawa
- Ken Kaseda
- Wataru Fujii
- Yoshihiro Tomomitsu
- Daigoro Hirohama
- Osamu Yamazaki
- Yuta Kochi
- Shigeru Shibata
1 Application
| Application ID | Title |
|---|---|
| 78657 | Establishment of eQTL/sQTL-based and trans-ancestry polygenic risk score for immune-related complex traits |
Enabling scientific discoveries that improve human health