|dc.contributor.author||Moorhouse, Rebecca Claire||
|dc.description.abstract||Cardiovascular disease (CVD) is highly prevalent in chronic kidney disease (CKD)
patients. Whilst this can in part be explained by the high incidence of traditional
CVD risk factors such as hypertension and diabetes evident in CKD patients, recent
focus has been on non-traditional risk factors and their role in CVD progression.
These include endothelial dysfunction, arterial stiffness, inflammation and oxidative
The potent vasoconstrictor endothelin-1 (ET-1) has been implicated in the
pathogenesis of CKD and the CVD associated with it. Further understanding of the
mechanisms by which it contributes to CKD and CVD pathogenesis, specifically its
interactions with non-traditional risk factors are still required. Additionally, the
potential applications of ET antagonists in renal disease have not been fully explored.
This thesis aims to investigate the role of ET-1 in the development of renal disease
and the associated inflammation, hypertension and vascular dysfunction through a
series of in vitro, in vivo and clinical studies.
I have demonstrated using in vitro techniques that murine macrophages (Mϕ) express
both endothelin A (ETA) and endothelin B (ETB) receptors but that ET-1 does not
elicit either a classical pro-inflammatory or alternative anti-inflammatory phenotype
in Mϕ. I was however, able to show that M display chemokinesis towards ET-1 and
M ETB receptors provide a novel clearance mechanism for ET-1 through receptor
mediated dynamin-dependent endocytosis
In an in vivo study I investigated whether ET-1 mediates the progressive renal injury
after renal ischaemia reperfusion injury (IRI) that leads to the development of CKD.
I demonstrated that endothelin A receptor antagonism provided long term beneficial
effects reducing blood pressure and preventing progressive kidney injury,
inflammation, and the development of fibrosis resulting from an episode of acute
kidney injury (AKI). Similar benefits were observed with calcium channel blockade,
suggesting hypertension may mediate some of the long term effects of renal IRI and
anti-hypertensive treatments could prevent the development of CKD after AKI.
Finally, in a clinical study I showed for the first time that CKD patients lack the
diurnal variation in arterial stiffness that is seen in matched subjects without CKD.
Alteration in the circadian variation of the ET-1 system may contribute to this.
In summary, my studies have furthered our understanding of the role of ET-1 in
CKD progression and the cardiovascular risk associated with it. Mϕ were shown to
express both ET receptors and a novel mechanism of ET-1 clearance was observed in
Mϕ. Using an in vivo model of AKI I was able to identify ETA receptor antagonism
as a novel therapeutic agent in preventing the development of CKD caused by AKI
where data are limited. Finally, alterations in the circadian rhythm of the
cardiovascular system is emerging as an important factor in disease pathogenesis.
Here the diurnal variation in arterial stiffness was described for the first time in a
group of CKD patients and matched controls.||en
|dc.publisher||The University of Edinburgh||en
|dc.relation.hasversion||Dhaun N, Moorhouse R, MacIntyre IM, et al. Diurnal variation in blood pressure and arterial stiffness in chronic kidney disease: the role of endothelin-1. Hypertension 2014;64(2):296–304.||en
|dc.relation.hasversion||Therapeutic potential of endothelin receptor antagonism in kidney disease Czopek A, Moorhouse R, Webb DJ, Dhaun N. Am J Physiol Regul Integr Comp Physiol. 2016 Mar 1;310(5):R388-97.||en
|dc.relation.hasversion||25 years of endothelin research: the next generation Emoto N, Vignon-Zellweger N, Lopes RA, Cacioppo J, Desbiens L, Kamato D, Leurgans T, Moorhouse R, Straube J, Wurm R, Heiden S, Ergul A, Yanagisawa M, Barton M. Life Sci. 2014 Nov 24;118(2):77-86.||en
|dc.relation.hasversion||Endothelin antagonism and its role in the treatment of hypertension Moorhouse R, Webb DJ, Kluth DC, Dhaun N. Curr Hypertens Rep. 2013 Oct;15(5):489-96.||en
|dc.subject||cardiovascular disease risk||en
|dc.title||Role of the endothelin system in the development of kidney disease and the associated inflammation, hypertension and vascular dysfunction||en
|dc.type||Thesis or Dissertation||en
|dc.type.qualificationname||PhD Doctor of Philosophy||en