Primary aldosteronism (PA) is caused by an excess of serum aldosterone due mainly to idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenomas (APA) in adulthood, and it is found in 5 - 13% of hypertension patients. Its main pathophysiological features are hypertension, altered potassium homeostasis, and accelerated target organ damages. We propose to develop a transgenic PA model that will revolutionize the study of this disease. A major challenge in PA research has been a lack of appropriate mouse model systems. Although some of the rodent hypertension models mimic PA pathology, these models require invasive surgical and/or drug treatments, therefore they have certain weaknesses and limitations. Besides these models, there are a few genetically modified mice which have been generated to show elevated aldosterone function and high blood pressure. These mice, however, show these pathological manifestations from early postnatal stages, and therefore do not replicate the conditions in the human PA patients, where the increases in aldosterone and blood pressure occur in adulthood for most patients. In order to develop a mouse model in which PA and hypertension can be induced in adults, we propose to develop a novel transgenic (Tg) mouse line. The Tg strategy employed for the development of this model will allow the controlled induction of the aldosterone synthase (Cyp11b2) gene in adrenal glands, leading to an excessive production of aldosterone. Since we will be able to induce Cyp11b2 expression at the age of our choice, for instance in adults, this model will allow us to replicate the pathology of human PA. Our overall hypothesis is that over-expression of the aldosterone synthase gene in adult mouse adrenal cortex causes primary aldosteronism. The immediate goals of this proposal are to generate the Tg mice and measure their serum aldosterone levels and blood pressure. To accomplish this goal, we propose two specific aims:
(Aim 1) To test the ability of the Cre-loxP conditional induction system to increase aldosterone using an in vitro adrenal cell culture model and (Aim 2) To determine in vivo effects of excessive aldosterone synthase expression in adult mouse adrenal cortex. The Tg mice produced in this project will be a unique and invaluable tool for PA and hypertension research.
We aim to generate an adult-onset primary aldosteronism mouse model using transgenic mouse technology in this proposal. Once generated, the mice may be used in primary aldosteronism and hypertension research as well as development of new class of anti-hypertension drugs.
