Jan-Sören Padberg1, Anne Wiesinger1, Giovana Seno di Marco1, Stefan Reuter1, Alexander Grabner1, Dominik Kentrup1, Alexander Lukasz1, Hans Oberleithner2, Hermann Pavenstädt1, Marcus Brand1, Philipp Kümpers3. 1. Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1 A1, 48149 Münster, Germany. 2. Institute of Physiology II, University of Muenster, Robert-Koch-Straße 27 b, 48149 Münster, Germany. 3. Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1 A1, 48149 Münster, Germany. Electronic address: philipp.kuempers@ukmuenster.de.
Abstract
BACKGROUND AND OBJECTIVES: The endothelial glycocalyx (eGC), a mesh of anionic biopolymers covering the luminal surface of endothelial cells, is considered as an intravascular compartment that protects the vessel wall against pathogenic insults in cardiovascular disease. We hypothesized that chronic kidney disease (CKD) is associated with reduced eGC integrity and subsequent endothelial dysfunction. METHODS & RESULTS: Shedding of two major components of the eGC, namely syndecan-1 (Syn-1) and hyaluronan (HA), was measured by ELISA in 95 patients with CKD (stages 3-5) and 31 apparently healthy controls. Plasma levels of Syn-1 and HA increased steadily across CKD stages (5- and 5.5-fold, respectively P < 0.001) and were independently associated with impaired renal function after multivariate adjustment. Furthermore, Syn-1 and HA correlated tightly with plasma markers of endothelial dysfunction such as soluble fms-like tyrosine kinase-1 (sFlt-1), soluble vascular adhesion molecule-1 (sVCAM-1), von-Willebrand-Factor (vWF) and angiopoietin-2 (P < 0.001). Experimentally, excessive shedding of the eGC, evidenced by 11-fold increased Syn-1 plasma levels, was also observed in an established rat model of CKD, the 5/6-nephrectomized rats. Consistently, an atomic force microscopy-based approach evidenced a significant decrease in eGC thickness (360 ± 79 vs. 157 ± 29 nm, P = 0.001) and stiffness (0.33 ± 0.02 vs. 0.22 ± 0.01 pN/nm, P < 0.001) of aorta endothelial cell explants isolated from CKD rats. CONCLUSION: Our findings provide evidence for damage of the atheroprotective eGC as a consequence of CKD and potentially open a new avenue to pathophysiology and treatment of cardiovascular disease in renal patients.
BACKGROUND AND OBJECTIVES: The endothelial glycocalyx (eGC), a mesh of anionic biopolymers covering the luminal surface of endothelial cells, is considered as an intravascular compartment that protects the vessel wall against pathogenic insults in cardiovascular disease. We hypothesized that chronic kidney disease (CKD) is associated with reduced eGC integrity and subsequent endothelial dysfunction. METHODS & RESULTS: Shedding of two major components of the eGC, namely syndecan-1 (Syn-1) and hyaluronan (HA), was measured by ELISA in 95 patients with CKD (stages 3-5) and 31 apparently healthy controls. Plasma levels of Syn-1 and HA increased steadily across CKD stages (5- and 5.5-fold, respectively P < 0.001) and were independently associated with impaired renal function after multivariate adjustment. Furthermore, Syn-1 and HA correlated tightly with plasma markers of endothelial dysfunction such as soluble fms-like tyrosine kinase-1 (sFlt-1), soluble vascular adhesion molecule-1 (sVCAM-1), von-Willebrand-Factor (vWF) and angiopoietin-2 (P < 0.001). Experimentally, excessive shedding of the eGC, evidenced by 11-fold increased Syn-1 plasma levels, was also observed in an established rat model of CKD, the 5/6-nephrectomized rats. Consistently, an atomic force microscopy-based approach evidenced a significant decrease in eGC thickness (360 ± 79 vs. 157 ± 29 nm, P = 0.001) and stiffness (0.33 ± 0.02 vs. 0.22 ± 0.01 pN/nm, P < 0.001) of aorta endothelial cell explants isolated from CKD rats. CONCLUSION: Our findings provide evidence for damage of the atheroprotective eGC as a consequence of CKD and potentially open a new avenue to pathophysiology and treatment of cardiovascular disease in renal patients.
Authors: Kerstin Ebefors; Robert J Wiener; Liping Yu; Evren U Azeloglu; Zhengzi Yi; Fu Jia; Weijia Zhang; Margaret H Baron; John C He; Börje Haraldsson; Ilse Daehn Journal: Kidney Int Date: 2019-05-22 Impact factor: 10.612
Authors: Jong Wook Song; Joseph Zullo; Mark Lipphardt; Matthew Dragovich; Frank X Zhang; Bingmei Fu; Michael S Goligorsky Journal: Nephrol Dial Transplant Date: 2018-02-01 Impact factor: 5.992
Authors: Rik H G Olde Engberink; Nienke M G Rorije; Jaap J Homan van der Heide; Bert-Jan H van den Born; Liffert Vogt Journal: J Am Soc Nephrol Date: 2014-10-07 Impact factor: 10.121
Authors: Alexandre Braga Libório; Marcelo Boecker Munoz Braz; Antonio Carlos Seguro; Gdayllon C Meneses; Fernanda Macedo de Oliveira Neves; Danielle Carvalho Pedrosa; Luciano Pamplona de Góes Cavalcanti; Alice Maria Costa Martins; Elizabeth de Francesco Daher Journal: Am J Trop Med Hyg Date: 2015-01-26 Impact factor: 2.345
Authors: Kristina M Niculovic; Linda Blume; Henri Wedekind; Elina Kats; Iris Albers; Stephanie Groos; Markus Abeln; Jessica Schmitz; Esther Beuke; Jan H Bräsen; Anette Melk; Mario Schiffer; Birgit Weinhold; Anja K Münster-Kühnel Journal: J Am Soc Nephrol Date: 2019-04-30 Impact factor: 10.121