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Title: Genetics of malignant hypertension and pathophysiological study in transgenic rats with inducible hypertension
Author: Kantachuvesiri, Surasak
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Hypertension afflicts 15-20% of the human population and exerts a significant impact on health care resources. Several studies both in humans and animal models suggested a genetic predisposition to hypertension and its complications including malignant hypertension (MH). In this study, two complementary approaches were employed to study the genetic factors and mechanisms of target organ damage in MH. In the first approach, the mouse Ren2 transgene was used to induce hypertension in different strains of rats and the incidence of MH was found to be dependent on genetic background. To identify the loci affecting the MH phenotype in rats, an informative genetic cross was carried out with phenotypic assessment and high throughput genome screening. QTL analysis identified a polygenic inheritance of MH lethality involving two modifier loci on chromosome 10 and 17 from the Fischer and Lewis strains, which encompass Ace and At1 genes, both logical candidates for involvement in the manifestation of the MH phenotype. The effects of the loci were consistent with multiplicative effects. Furthermore, a difference in plasma ACE activity was found in rats inheriting Fischer and Lewis loci and supported the association of ACE and MH. To facilitate the study of the etiology of vascular lesion in MH, rats with inducible hypertension were generated. The strategy utilized the cytochrome P450, Cyp1a1 promoter to drive expression of Ren2 in transgenic rats. Transgene expression was thereby rendered inducible by xenobiotics, such as indole-3 carbinol (13C) and 3-methylcholanthrene. The level and duration of hypertension can be regulated in these rats by adjusting the dosage and nature of inducer. Kinetics study of plasma and tissue renin suggested that tissue uptake and activation of prorenin was implicated in development of hypertension. The rats exhibited clinical and pathological features of malignant hypertension upon induction with continuous dietary 13C administration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available