Show simple item record

dc.contributor.authorWhitworth, Caroline Elizabethen
dc.date.accessioned2018-01-31T11:40:09Z
dc.date.available2018-01-31T11:40:09Z
dc.date.issued1995en
dc.identifier.urihttp://hdl.handle.net/1842/27656
dc.description.abstractThe transgenic rat line TGR(mREN2)27 has been previously shown to develop severe hypertension as a consequence of over -expression of the mouse Ren -2 renin gene (Mullins et al 1990). It was observed that an alteration in phenotype occurred in hybrids (HanRen2/Edin --) derived from crossing homozygous Ren -2 transgenic rats with the Edinburgh Sprague -Dawley strain of rats. Investigations into this phenotypic change revealed it to be due to spontaneous development of malignant phase hypertension. Furthermore the incidence of the malignant hypertensive phenotype was altered by the genetic background into which the transgene was introduced.en
dc.description.abstractThe introduction of this thesis has reviewed the literature on the genetics of human essential hypertension and rat models of genetic hypertension, the role of the kidney in essential hypertension and the pathogenesis of malignant hypertension. Techniques in molecular biology which include transgenesis have been used to investigate the role of individual genes in blood pressure regulation. In this context the literature concerning the transgenic rat line TGR(mREN2)27 was extensively reviewed.en
dc.description.abstractThe heterozygote cross HanRen2/Edin -- was found to develop malignant phase hypertension within a relatively narrow age range. Seventy -three percent of male and 52% of female HanRen2/Edin -- developed malignant hypertension. In contrast, other heterozygote crosses HanRen2/Han-- and HanRen2/Lew -- had an incidence in males of 18% and 0% and in females of 4% and 0% respectively. Telemetry was used to record blood pressure continuously in unrestrained conscious rats and demonstrated an accelerated rise in blood pressure in rats with clinical features of malignant phase hypertension. Histopathology showed fibrinoid necrosis and myo- intimal proliferation of afferent arterioles and small renal arteries. An associated deterioration in renal function occurred with a rise in plasma urea and creatinine. TGR(mREN2)27 normally have a suppressed renal renin -angiotensin system but in malignant phase affected animals had a significant elevation of plasma renin, angiotensin II and aldosterone. Immunohistochemistry demonstrated increased renin at the site of the afferent arterioles near the vascular poles of glomeruli. Blood films demonstrated a microangiopathic haemolytic anaemia. A genetic basis for the differing incidence of malignant phase between the three heterozygote crosses was further supported by the results of an analytical cross set up to segregate Edinburgh Sprague -Dawley alleles. Results suggested that malignant phase hypertension complicated benign hypertension due to the effects of one or possibly two genetic loci.en
dc.description.abstractA further study looked at the role of endothelin in malignant hypertension. Previous investigators had suggested that endothelin may be involved in the pathogenesis of malignant phase hypertension. RNase protection assays demonstrated increased expression of endothelin- 1 mRNA in kidneys from malignant hypertensive rats. Chronic inhibition of endothelin receptors using an oral non -specific endothelin receptor antagonist (Bosentan) did not prevent or reduce the transition from benign to malignant phase hypertension. It would therefore appear that endothelin synthesis occurs in response to the transition to malignant hypertension but it is not a central initiating factor.en
dc.description.abstractIn conclusion, this is a representative model showing many of the characteristics of malignant phase hypertension in humans. The differing incidence between transgenic Ren -2 crosses appeared to be a consequence of genetic factor(s). This may therefore be another example of a genetic pre -disposition to develop target organ damage from hypertension.en
dc.publisherThe University of Edinburghen
dc.relation.isreferencedbyAlready catalogueden
dc.subjectAnnexe Thesis Digitisation Project 2017 Block 16en
dc.titleMalignant hypertension in the transgenic Ren-2 raten
dc.typeThesis or Dissertationen
dc.type.qualificationlevelen
dc.type.qualificationnameMD Doctor of Medicineen


Files in this item

This item appears in the following Collection(s)

Show simple item record