Effects of Chronic Kidney Disease on Nanomechanics of the Endothelial Glycocalyx Are Mediated by the Mineralocorticoid Receptor

Benedikt Fels*, Arne Beyer, Violeta Cazaña-Pérez, Teresa Giraldez, Juan F. Navarro-González, Diego Alvarez de la Rosa, Franz Schaefer, Aysun K. Bayazit, Łukasz Obrycki, Bruno Ranchin, Johannes Holle, Uwe Querfeld, Kristina Kusche-Vihrog

*Corresponding author for this work
2 Citations (Scopus)

Abstract

Endothelial mechanics control vascular reactivity and are regulated by the mineralocorticoid receptor (MR) and its downstream target, the epithelial Na+ channel (ENaC). Endothelial dysfunction is a hallmark of chronic kidney disease (CKD), but its mechanisms are poorly understood. We hypothesized that CKD disrupts endothelial mechanics in an MR/ENaC-dependent process. Methods: Primary human endothelial cells were cultured with uremic serum derived from children with stage 3–5 (predialysis) CKD or adult hemodialysis (HD) patients or healthy controls. The height and stiffness of the endothelial glycocalyx (eGC) and cortex were monitored by atomic force microscopy (AFM) using an ultrasensitive mechanical nanosensor. Results: In a stage-dependent manner, sera from children with CKD induced a significant increase in eGC and cortex stiffness and an incremental reduction of the eGC height. AFM measurements were significantly associated with individual pulse wave velocity and serum concentrations of gut-derived uremic toxins. Serum from HD patients increased MR expression and mechanical stiffness of the endothelial cortex, an effect reversed by MR and ENaC antagonists, decreased eNOS expression and NO bioavailability, and augmented monocyte adhesion. Conclusion: These data indicate progressive structural damage of the endothelial surface with diminishing kidney function and identify the MR as a mediator of CKD-induced endothelial dysfunction.

Original languageEnglish
Article number10659
JournalInternational Journal of Molecular Sciences
Volume23
Issue number18
ISSN1661-6596
DOIs
Publication statusPublished - 09.2022

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 205-04 Physiology
  • 205-16 Nephrology
  • 201-03 Cell Biology

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