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Title: Investigation and characterisation of renin-dependent transgenic rat models of hypertension and left ventricular hypertrophy
Author: Ryding, Alisdair D. S.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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We studied cardiac function in a novel conditional transgenic rat model of hypertension, TGRcyplalren2, during the development of LVH. In this model the transgene comprises mouse ren2 cDNA under the transcriptional control of the cytochrome p450 promoter cyplal, rendering it inducible by dietary arylhydrocarbons such as indole-3 carbinol (I3C). Initial studies demonstrated that 0.15% I3C (w/w) induced a chronic hypertensive phenotype with concentric LVH. No change in LV function was detected by echocardiography or LV catheterisation. Telemetric ECG data demonstrated significant electrical remodelling, but only a minor increase in arrhythmias. We next investigated the effect of FK506, a calcineurin inhibitor, on the cardiac hypertrophic response during short-term studies using 0.13% I3C (w/w). Contrary to all previous reports concerning the use of this drug in models of hypertension we found that FK506 treatment abolished hypertension, as well as inhibiting vascular injury and end organ damage. At present we are unable to explain the precise mechanism by which this occurs. In separate studies we sought to investigate the mechanism by which prorenin contributes to cardiac hypertrophy in transgenic rats. Current evidence indicates that glycosylated prorenin can be imported and activated by cardiomyocytes, via the mannose-6 phosphate receptor. However this mechanisms does not account for the observation that non-glycosylated mouse prorenin-2 is also taken up by cardiomyocytes in vitro and in rats transgenic for ren2. We hypothesised that separate pathways probably exist for glycosylated and non-glycosylated prorenins. To investigate this further we produced enzymatically active recombinant mouse ren2 in a baculovirus expression system. Unfortunately further studies of prorenin/cardiomyocyte physiology were presented by problems with recombinant protein yield and purity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available