The renin-angiotensin system (RAS) has been shown to play an integral role in the regulation of blood pressure and volume homeostasis in mammals. Molecular genetic studies support a role for the RAS genes in contributing to a predisposition to hypertension, as well as myocardial infarction and cardiac hypertrophy, in human populations and hypertensive rats. in addition to the well established role of the RAS as an endocrine system, a concept has evolved that suggests that individual tissue renin- angiotensin systems may also exist. These intrinsic tissue RAS are defined by the potential for the local generation and action of angiotensin-II and are thought to exist in tissues which express each RAS gene mRNA or contain each RAS gene product. It has been defintively shown that the kidney is one such organ and an intrinsic renal RAS has been proposed to regulate renal blood flow, glomerular filtration, sodium homeostasis, and tubuloglomerular balance. The concept remains controversial because it has previously been difficult to separate the effects of the endocrine (or systemic) RAS from its effects in individual organs. We propose to take a molecular genetic approach to this problem by using transgernc knock-out, and tissue-specific knock-out mice to test the hypothesis that intrinsic tissue renin-angiotensin systems, in particular the renal renin- angiotensin system, play an integral role in the regulation of basal blood pressure and renal function and may participate in the development or maintenance of hypertension. To accomplish this we propose to generate transgenic and knock-out models in which the levels of circulating or renal angiotensinogen are tissue-specifically increased, decreased or ablated and then characterize the changes in blood pressure and renal function. These manipulations will be made in normotensive inbred mice, in renin-dependent human reniii/human angiotensinogen transgenic mice, and in non-renin dependent hypertensive (BPH-2) mice, and will make extensive use of preexisting transgenic, knockout, and genetically manipulated mouse strains. The experiments proposed herein will provide novel tools and techniques for assessing gene function and meld together diverse disciplines of molecular genetics, molecular biology, pharmacology, and physiology. The studies and techniques developed in this proposal will have definite and important implications for the analysis of novel loci and genes identified through molecular genetic studies to be linked to multigenic traits such as hypertension.
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