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Abstract: TH-PO148

Fibroblast Growth Factor 23 Induces Endothelial Glycocalyx Collapse and Cortex Stiffening in Patients on Hemodialysis: A Major Role for the C-Terminal Fragment

Session Information

  • CKD-MBD: Targets and Outcomes
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Koch, Josephine, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Kunze, Tamara, Universitat zu Lubeck, Lubeck, Schleswig-Holstein, Germany
  • Vahldieck, Carl, Universitat zu Lubeck, Lubeck, Schleswig-Holstein, Germany
  • Fels, Benedikt, Universitat zu Lubeck, Lubeck, Schleswig-Holstein, Germany
  • Dam, Wendy, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Franssen, Casper F.M., Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • van den Born, Jacob, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands
  • Kusche-Vihrog, Kristina, Universitat zu Lubeck, Lubeck, Schleswig-Holstein, Germany
Background

Cardiovascular disease and endothelial dysfunction (ED) are common in patients with chronic kidney disease (CKD). CKD patients have elevated plasma fibroblast growth factor 23 (FGF23) which associates with higher incidence of cardiovascular events. Hallmarks of ED are damage of the endothelial glycocalyx (eGC) and cortex stiffening. Here we evaluated whether FGF23 directly induces changes in eGC and underlying endothelial cortex.

Methods

Human umbilical vein endothelial cells were incubated with uremic sera from hemodialysis patients with low (≤2,000 RU/mL; n=6) or high (≥30,000 RU/mL; n=6) FGF23, and with recombinant intact FGF23 and c-terminal FGF23 (each 30 ng/mL). Height of the eGC and stiffness of the eGC and cortex were assessed by atomic force microscopy. eGC components and cortical F-actin were quantified by immunofluorescence stainings.

Results

Patient sera with high FGF23 reduced eGC height (-12%; P<0.0001), increased eGC stiffness (+63%; P<0.0001) and enhanced cortical stiffening (+16%; P<0.0001) compared to patient sera containing low FGF23. Recombinant c-terminal FGF23 but not intact FGF23 induced similar effects compared to unstimulated controls (eGC height: -37%; P<0.0001; eGC stiffness: +69%; P<0.0001; cortical stiffness: +32%; P<0.0001). Quantification of three eGC glyco-epitopes revealed no differences upon intact FGF23 or c-terminal FGF23 incubation. F-actin increased by 36% after c-terminal FGF23 stimulation (P<0.0001), whereas intact FGF23 did not affect F-actin. Specificity was demonstrated by FGF23 blocking antibodies.

Conclusion

Our results indicate that c-terminal FGF23 and not intact FGF23 induces collapse of the eGC and stiffens the cortex. Our findings suggest c-terminal FGF23 having a pathophysiological role in the development of ED in hemodialysis patients.

Funding

  • Government Support – Non-U.S.