The protein-bound uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) increases erythrocyte osmotic fragility through interaction with the mechanosensitive channel Piezo1.

Abstract

Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, shares structural similarities with the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). We explored the hypothesis that CMPF at a concentration seen in uremia activates Piezo1 located on red blood cells (RBC). We incubated RBC from five healthy individuals with either Jedi1 or CMPF (both 87 M), with or without the Piezo1 inhibitor GsMTx-4 (2 M), and quantified the cells osmotic fragility. Our results indicate that compared to controls (i.e., RBC incubated with buffer), both Jedi1 and CMPF increase the osmotic fragility of RBC (i.e., reduce their resistance to osmotic stress). Effects of Jedi1 and CMPF were reversed to the control level by GsMTx-4. These results indicate a role of Piezo1 in augmenting RBC osmotic fragility and modulation of this effect by Jedi1 and CMPF. Our findings open the possibility that CMPF may act as an endogenous chemical activator of Piezo1.