Vitamin D attenuates endothelial dysfunction in uremic rats and maintains human endothelial stability

Marc Vila Cuenca, Evelina Ferrantelli, Elisa Meinster, Stephan M. Pouw, Igor Kovačević, Renné X. de Menezes, Hans W. Niessen, Robert H.J. Beelen, Peter L. Hordijk, Marc G. Vervloet

Research output: Contribution to journalArticleAcademicpeer-review

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 a-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 a-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 a-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.

Original languageEnglish
Article numbere008776
JournalJournal of the American Heart Association
Volume7
Issue number17
DOIs
Publication statusPublished - 1 Sep 2018

Cite this

@article{53c6f09846934427b75e9989fbad90ff,
title = "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 a-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 a-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 a-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.",
keywords = "Chronic kidney disease, Endothelial dysfunction, Klotho, Vitamin D",
author = "Cuenca, {Marc Vila} and Evelina Ferrantelli and Elisa Meinster and Pouw, {Stephan M.} and Igor Kovačević and {de Menezes}, {Renn{\'e} X.} and Niessen, {Hans W.} and Beelen, {Robert H.J.} and Hordijk, {Peter L.} and Vervloet, {Marc G.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1161/JAHA.118.008776",
language = "English",
volume = "7",
journal = "Journal of American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "17",

}

Vitamin D attenuates endothelial dysfunction in uremic rats and maintains human endothelial stability. / Cuenca, Marc Vila; Ferrantelli, Evelina; Meinster, Elisa; Pouw, Stephan M.; Kovačević, Igor; de Menezes, Renné X.; Niessen, Hans W.; Beelen, Robert H.J.; Hordijk, Peter L.; Vervloet, Marc G.

In: Journal of the American Heart Association, Vol. 7, No. 17, e008776, 01.09.2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Vitamin D attenuates endothelial dysfunction in uremic rats and maintains human endothelial stability

AU - Cuenca, Marc Vila

AU - Ferrantelli, Evelina

AU - Meinster, Elisa

AU - Pouw, Stephan M.

AU - Kovačević, Igor

AU - de Menezes, Renné X.

AU - Niessen, Hans W.

AU - Beelen, Robert H.J.

AU - Hordijk, Peter L.

AU - Vervloet, Marc G.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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 a-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 a-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 a-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.

AB - 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 a-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 a-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 a-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.

KW - Chronic kidney disease

KW - Endothelial dysfunction

KW - Klotho

KW - Vitamin D

UR - http://www.scopus.com/inward/record.url?scp=85054475134&partnerID=8YFLogxK

U2 - 10.1161/JAHA.118.008776

DO - 10.1161/JAHA.118.008776

M3 - Article

VL - 7

JO - Journal of American Heart Association

JF - Journal of American Heart Association

SN - 2047-9980

IS - 17

M1 - e008776

ER -