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 <i>Ren2</i> 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 <i>Ace </i>and <i>At1</i> 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, <i>Cyp1a1</i> promoter to drive expression of <i>Ren2</i> 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.
Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:653204 |
Date | January 1999 |
Creators | Kantachuvesiri, Surasak |
Publisher | University of Edinburgh |
Source Sets | Ethos UK |
Detected Language | English |
Type | Electronic Thesis or Dissertation |
Source | http://hdl.handle.net/1842/12101 |
Page generated in 0.0013 seconds