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Abstract: TH-PO950

3-Carboxy-4-Methyl-5-Propyl-2-Furanpropionate (CMPF), an Endogenous Protein-Bound Uremic Solute, Renders Erythrocyte Osmotically More Fragile, Possibly Through a Piezo1 Pathway

Session Information

Category: Anemia and Iron Metabolism

  • 200 Anemia and Iron Metabolism

Authors

  • Van Spitzenbergen, Beatriz Akemi Kondo, Pontificia Universidade Catolica do Parana, Curitiba, PR, Brazil
  • Ferreira Dias, Gabriela, Renal Research Institute, New York, New York, United States
  • Grobe, Nadja, Renal Research Institute, New York, New York, United States
  • Moreno-Amaral, Andrea Novais, Pontificia Universidade Catolica do Parana, Curitiba, PR, Brazil
  • Kotanko, Peter, Renal Research Institute, New York, New York, United States
Background

Shortened red blood cell (RBC) life span contributes to renal anemia and may be caused by uremia-induced premature RBC death (eryptosis). Recently, it was hypothesized that the uremic solute CMPF interacts with the Piezo1 mechanoreceptor on the RBC surface due to CMPF’s structural similarity with Jedi1, a well-characterized synthetic Piezo1 agonist (Kotanko et al., 2022). In this study, we compared the effects of Jedi1 and CMPF on RBC osmotic fragility.

Methods

RBC from 5 healthy subjects were incubated for 30 min with CMPF or Jedi1 (both at concentrations of 87 µM) in phosphate-buffered saline with 4% human serum albumin. RBC incubated without CMPF or Jedi1 were negative controls. Subsequently, RBC suspensions were incubated in NaCl solutions of increasing osmolarity (NaCl 3 to 9 g/L). Free hemoglobin was measured in the supernatant by spectrophotometry at 540 nm. The data were fitted to a 4-parameter logistic regression curve to obtain the osmotic fragility index (IC50). IC50 is defined as the NaCl concentration that causes 50% hemolysis.

Results

RBC incubation with CMPF or Jedi1 increased IC50 (i.e., increased osmotic fragility) when compared to the negative control (Table 1). The IC50 increase was most pronounced in RBC incubated with CMPF.

Conclusion

Our findings suggest that CMPF - an endogenous metabolite and uremic solute - may increase RBC osmotic fragility, possibly through a Piezo1 pathway. Understanding the molecular mechanisms involved may aid the developing new therapeutic approaches to renal anemia.

Table 1 – RBC osmotic fragility index (IC50) under different experimental conditions
Experimental conditionIC50 mean±SD (95% CI)Mean IC50 difference (95%CI) to controlsp-value
Negative control4.57 ± 0.31 (4.18 – 4.97)Not applicableNot applicable
Jedi1 (87µM)5.02 ± 0.28 (4.66 – 5.37)0.45 (0.06 – 0.83)0.031
CMPF (87μM)5.57 ± 0.39 (5.09 – 6.06)1.00 (0.61 – 1.38)0.002