Chronic kidney disease (CKD) is growing global public health problem
affecting 1 in 10 adults in developed countries and recognised as an
important risk factor for cardiovascular disease (CVD) development. CVD is
the main cause of death among CKD patients. Endothelial injury and
dysfunction are critical steps in atherosclerosis, a major CVD. Oxidative
stress (increased level of reactive oxygen species, ROS) has been
associated with CVD development. Intravenous (IV) iron preparations are
widely used in the management of CKD mediated anaemia, and have been
associated with increased oxidative stress and cellular dysfunction.
This study examined the effect of pharmacologically-relevant
concentrations of IV Venofer (iron sucrose) or IV Ferinject (Ferric
carboxymaltose, FCM) on primary human umbilical vein endothelial cell
(HUVEC) activation/damage and on intracellular ROS generation as well as
studying the potential mechanisms responsible. Data from TUNEL assay and
Annexin V-FITC/PI staining showed that, IV FCM had no effect, but IV iron
sucrose increased HUVEC apoptosis at 24hr. IV iron sucrose inhibited cell
proliferation and reduced cell viability. Both compounds induced EC
activation through sustained activation of p38 MAPK and up-regulation of
ICAM-1 and VCAM-1. Additionally, the compounds induced significant
increase in total ROS and superoxide anion production, which was
attenuated by the anti-oxidant N-acetylcysteine (NAC). P38 MAPK showed
up-regulation of pro-apoptotic protein Bax and down-regulation of antiapoptotic
Bcl-2 protein in HUVEC treated with IV iron sucrose and p38
inhibition reversed these effects.
In summary, these results suggest that IV iron sucrose causes more
severe EC injury than IV FCM. However, both IV iron preparations induced
intracellular ROS and superoxide anion generation in HUVEC leading to EC
activation/dysfunction, providing a potential explanation for vascular damage
in CKD patients.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/14325 |
| Date | January 2015 |
| Creators | Hadeiba, Tareg Hadi Ahmed |
| Contributors | Graham, Anne M |
| Publisher | University of Bradford, Faculty of Life Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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