Nephrology, dialysis, transplantation
20 Nov 2024 The uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) may enhance eryptosis and increase erythrocyte osmotic fragility through potential activation of Piezo1RESULTSIncubation of RBC with CMPF and Jedi1 significantly increased RBC osmotic fragility, an effect prevented by GsMTx-4. At 6.0 g/L NaCl, incubation with CMPF and Jedi1 increased exposure of phosphatidylserine and elevated icCa2+ levels of RBC, indicating increased eryptosis. Notably, at an isotonic NaCl concentration of 9.0 g/L, CMPF - but not Jedi1 - significantly increased RBC phosphatidylserine exposure and icCa2+ levels; both effects were diminished by GsMTx-4.BACKGROUND AND HYPOTHESISIn patients with advanced chronic kidney disease (CKD), the lifespan of red blood cells (RBC) is often shortened, a condition attributed to the "uremic milieu." We reported recently that the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) shares structural similarities with Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, whose activation increases calcium influx into cells. Against this backdrop, we hypothesized that CMPF may induce premature RBC death (eryptosis) through prolonged CMPF-induced activation of Piezo1 located on RBC. To test this hypothesis, we explored if CMPF, at concentrations found in uremia, interacts with Piezo1 located on RBC, increases intracellular calcium (icCa2+), and induces eryptosis.CONCLUSIONOur findings support the hypothesis that CMPF may function as an endogenous activator of Piezo1, increase icCa2+ levels, trigger eryptosis, and, through this pathway, possibly shorten the RBC life span. To what extent these in vitro findings are operative in advanced CKD warrants clinical studies.METHODSRBC from healthy individuals were incubated with CMPF or Jedi1 (both at a concentration of 87 µM), in the presence or absence of the Piezo1 inhibitor GsMTx-4 (2 µM). We challenged RBC osmotically through incubation in solutions of NaCl at concentrations between 3.0 and 9.0 g/L and determined their osmotic fragility. Using flow cytometry, we quantified in incubated RBC icCa2+ levels and phosphatidylserine exposure, a cellular marker of eryptosis.
