Aldosterone plays a significant role in the development of hypertension and cardiovascular damage. Primary aldosteronism is a form of hypertension characterized by the autonomous and excessive secretion of aldosterone by the adrenal zona glomerulosa. Studies throughout the world have shown that the incidence is between 7-10% of essential hypertensives, and higher in patients with refractory hypertension. The rate limiting enzyme in the control of aldosterone biosynthesis in the zona glomerulosa of the adrenal is the product of the CYP11B2 gene, aldosterone synthase. Aldosterone synthase is regulated at the transcriptional level and we and others have described multiple genes that contribute to the transcriptional regulation of the expression. MicroRNAs are a class of regulators of gene expression that have recently been found to be crucial for pancreatic islet development, insulin secretion, adipogenesis, and B-cell development, and others. The H295 cell is a human adrenal carcinoma and responds to aldosterone secretagogues. We demonstrated that 35 different microRNAs are highly expressed in H295 cells and initial microarray studies suggest that their expression is up or down regulated by aldosterone secretagogues. We have studied mir21, one of these microRNAs, and found that it is most highly expressed in the zona glomerulosa of the rat adrenal and is upregulated by incubation with angiotensin II. Overexpression of mir21 in H295R cells enhances aldosterone synthesis in response to angiotensin II, suggesting that mir21 plays a role in the regulation of aldosterone biosynthesis. We have recently discovered a new miRNA that is expressed in the rat zona glomerulosa from a non-coding RNA that we cloned that is highly regulated by angiotensin II. Our hypotheses are: "Genes that regulate the transcription and translation of the CYP11B2 gene encoding Aldosterone Synthase and directly or indirectly modulate aldosterone biosynthesis are regulated by adrenal glomerulosa-specific MicroRNAs." In addition, "MicroRNAs regulate adrenal zona glomerulosa cellular proliferation and differentiation resulting in zona glomerulosa remodeling" in response to physiological need, such as sodium deprivation. The following specific aims are proposed to test these hypotheses: 1. Study the expression of miRNAs identified in functional microarray screens of rat zona glomerulosa and study the regulation of the most promising candidate miRNAs during adrenal remodeling induced by chronic sodium depletion, angiotensin II, ACTH infusion, and adrenal decommissioning. 2. Characterize the miRNAs that participate in the regulation of the expression of the aldosterone synthase and/or aldosterone biosynthesis in the H295R adrenal cortical carcinoma cell line.
Aldosteronism is the most common form of secondary hypertension, accounting for about 7-10% of unselected patients with hypertension World-wide. In addition to increasing blood pressure, levels of aldosterone in excess of physiological need, even when relatively mild, are associated with a greater cardiovascular, renal and cerebrovascular pathology than that associated with similar levels of blood pressure increase without excessive aldosterone. Treatment remains limited to mineralocorticoid receptor antagonists. Identifying genes involved in adrenal remodeling and aldosterone production will allow us to address the pathogenesis of Idiopathic Hyperaldosteronism directly. Cells of the adrenal cortex, like many endocrine and endocrine hormone-driven organs, must proliferate, regulate hormone synthesis and undergo apoptosis in response to ever-changing physiological circumstances and need. The science of miRNAs is still very young. The potential that this class of translational regulators are important in other systems that naturally undergo cyclic changes in cell number, size and metabolic activity, and thus in the etiology of derangements of these, particularly cancer, is very great and of general importance to health care. An inherent strength of the proposal lies in the extensive experience of the team of investigators. The experiments proposed are further strengthened by preliminary data, which include a recent publication in Endocrinology, that provide compelling evidence for miRNA-dependent modulation of aldosterone secretion. However, several concerns about the research plan, including the number of miRNAs proposed to be investigated coupled with the lack of a detailed strategy of how efforts will be focused, the lack of key reagents (antibodies to assess aldosterone synthase and 11b-hydroxylase protein expression), and the absence of approaches to address the limitations of many of the proposed experiments temper enthusiasm for the application.
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