Studies on the regulation of gene expression of tissue renin-angiotensin systems.
thesisposted on 19.11.2015, 08:49 by Martin Patrick. Kelly
The classic view of the renin-angiotensin system is that of a circulating, systemic hormonal cascade regulating blood pressure and extracellular fluid volume. However, increasing evidence has led to the suggestion that functional renin-angiotensin systems comprising some or all of the components of the enzymatic pathway may exist within several individual organs or tissues. The purpose of the work presented in this thesis was (i). to confirm renin- angiotensin system gene expression in various tissues (ii). to examine the effects of inhibition at different levels on expression (iii). to investigate the effects of experimental post-infarction heart failure on tissue renin-angiotensin systems and to see whether ACE inhibitor treatment, which improves this condition, influences gene expression. In the work presented, first a systematic study of rat tissues by Northern blotting and RT-PCR demonstrated the expression of mRNA for components of the renin-angiotensin system in several tissues, supporting the concept of their existence and resolving controversy over the potential for expression in certain tissues. Subsequently, both acute and chronic pharmacological blockade of the cascade by an ACE inhibitor demonstrated differential regulation of the renin-angiotensin system in different tissues. In farther studies, blockade of the cascade at three different levels in the marmoset confirmed differential regulation of specific components in different tissues. In contrast to previous reports, induction of experimental heart failure in rats followed by administration of an ACE inhibitor resulted in a 1.6 fold increase in renal angiotensinogen mRNA and a change in cardiac ACE mRNA was not seen with heart failure. A reduction in mortality was also associated with ACE inhibitor treatment. The results obtained raise interesting questions both of the role of tissue renin- angiotensin systems in contributing to the pathophysiology of disease states and mediating the effects of pharmacological blockade of the renin-angiotensin system, and more generally regarding their organisation.