Role of Mineralocorticoids in Hypertension

$259,000R01FY2005HLNIH

University Of Mississippi Medical Center, Jackson MS

Investigators

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Abstract

DESCRIPTION (provided by applicant): Primary aldosteronism is the most common form of secondary hypertension in the human, yet the regulation of aldosterone secretion remains incompletely understood. The H295R cell line developed from a human adrenal cell carcinoma is the only adrenal cell line that retains pluripotential and differentiated properties. When stimulated with angiotensin II or potassium the H295R secretes aldosterone. We used cDNA microchip arrays to identify genes that are upregulated in H295R cells after incubation with angiotensin II for 3 hr to study the resulting changes in gene expression. We confirmed the up-regulation of 11 genes stimulated by angiotensin II by using real time PCR. The purpose of this proposal is to evaluate the role of four of these genes in the regulation of aldosterone secretion: c6orf37, neuritin and MBLL. These three genes were selected because they have features suggesting that they are involved in development or in the regulation of gene splicing, or that are highly expressed in other steroidogenic tissues, but in all cases their functions are unknown. The specific aims involve the study of the potential roles for each gene in aldosterone biosynthesis. A major tool in this endeavor will be the over-expression of the gene of interest in H295R cells. As transfection efficiency with plasmids is very low in the H295R, lentiviral vectors will be used for the transfections. Expression of the target genes will be suppressed using lentiviral vectors carrying siRNAs for each of the genes. Expression of each of these genes will also be measured in isolated rat adrenal cells stimulated with angiotensin II, potassium and ACTH in vitro. Adrenals from rats subjected to various manipulations of sodium intake will also be used to measure the regulation of the expression of these genes in vivo. Preliminary data show that suppression of the c6orf37 with siRNA in H295R cells results in a marked potentiation of aldosterone secretion induced by angiotensin II. We will study the mechanism of potentiation.

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