Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability.

Abstract

Background Dysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease ( CKD ). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD , not only by direct effects on the endothelium but also by an increment of α-Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia-induced endothelial damage and the extent to which this was dependent on increased α-Klotho concentrations. Methods and Results In a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial-gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α-Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real-time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro-permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial-cadherin-based cell-cell junctions and diminished F-actin stress fiber organization, preventing the formation of endothelial intracellular gaps. Conclusions Our results demonstrate that paricalcitol attenuates the CKD -induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell-cell interactions.

• Authors: Marc Vila Cuenca, Evelina Ferrantelli, Elisa Meinster, Stephan M Pouw, Igor Kovačević, Renee X de Menezes, Hans W Niessen, Robert H J Beelen, Peter L Hordijk, Marc G Vervloet
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 7 Issue 17 Pg. e008776 (09 04 2018) ISSN: 2047-9980 [Electronic] England
• PMID: 30371149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Cadherins
• Ergocalciferols
• paricalcitol
• Glucuronidase
• Klotho Proteins

Topics

• Actins (drug effects, metabolism)
• Animals
• Aorta, Thoracic (drug effects, metabolism)
• Cadherins (drug effects, metabolism)
• Capillary Permeability (drug effects)
• Disease Models, Animal
• Endothelium, Vascular (drug effects, metabolism, physiopathology)
• Ergocalciferols (pharmacology)
• Glucuronidase (drug effects, metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• Intercellular Junctions (drug effects, metabolism)
• Klotho Proteins
• Rats
• Renal Insufficiency, Chronic (metabolism)
• Stress Fibers (drug effects)
• Uremia (metabolism)
• Vitamin D Deficiency (metabolism)