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dc.contributor.advisorWebb, David
dc.contributor.authorMoorhouse, Rebecca Claire
dc.date.accessioned2018-01-09T16:23:47Z
dc.date.available2018-01-09T16:23:47Z
dc.date.issued2016-07-02
dc.identifier.urihttp://hdl.handle.net/1842/25867
dc.description.abstractCardiovascular 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 stress. 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.contributor.sponsorotheren
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionDhaun 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.hasversionTherapeutic 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.hasversion25 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.hasversionEndothelin 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.subjectEndothelin-1en
dc.subjectkidney diseaseen
dc.subjectmacrophagesen
dc.subjectcardiovascular disease risken
dc.titleRole of the endothelin system in the development of kidney disease and the associated inflammation, hypertension and vascular dysfunctionen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31en
dcterms.accessRightsRestricted Accessen


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