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RNA-binding proteins regulate aldosterone homeostasis in human steroidogenic cells

ABSTRACT: AngiotensinII (AngII) binds to the type I angiotensin receptor in the adrenal cortex to initiate a cascade of events leading to the production of aldosterone, a master regulator of blood pressure and volume. While the key signaling pathways, transcription factors, and steroidogenic enzymes necessary for adrenocortical production have been identified, surprisingly little is known about post-transcriptional regulation of this process. To investigate this question, we performed a high-resolution RNA-seq time course of the AngII stimulation response in a steroidogenic human cell line (H295R). We identified twelve temporally distinct groups of gene expression responses important for various steps of aldosterone production. AngII response kinetics for many of these mRNAs revealed a coordinated increase in both synthesis and decay. These findings were validated in primary human adrenocortical cells stimulated ex vivo with AngII or ACTH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163801 | GEO | 2021/06/01

REPOSITORIES: GEO

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Project description:Steroidogenic acute regulatory protein (Star) facilitates cholesterol transfer into the inner mitochondrial membrane in the acute and regulated production of steroid hormones. Mice lacking Star (Star-/-) share the phenotypes with patients with congenital lipoid adrenal hyperplasia such as compromised production of steroid hormones and florid accumulation of cholesterol esters in adrenal glands and gonads. To define specific patterns of molecular changes with disruption of Star, we performed a transcriptome analysis of steroidogenic cells in adrenal glands. We harvested adrenal glands at E17.5 or 18.5 from seven wild-type (Star+/+) mice or four Star-/- mice having the transgene targeting enhanced green fluorescent protein (eGFP) under the control of regulatory sequences of mouse Star gene. Steroidogenic cells were selectively isolated by fluorescent-activated cell sorting. The gene expression profile of the fluorescence-positive cells was obtained with Agilent Whole Mouse Genome Microarray and was confirmed by quantitative real-time PCR. We identified 961 and 622 genes that were significantly up-regulated and down-regulated, respectively, in Star-/- mice compared with Star+/+ mice (fold difference ≥2, p value of Student t test <0.05, and Benjamini-Hochberg false discovery rate of multiple comparison test <0.2). In Star-/- mice, expression levels of genes involved in cholesterol mobilization and efflux or immune response as antigen presenting cells were significantly increased, and transition from fetal to adult adrenocortical cells were significantly decreased, whereas those of genes related to steroid hormone biosynthesis or cholesterol biosynthesis and influx were not significantly changed. The trancriptome analysis revealed hitherto undescribed characteristic changes in adrenocortical cells and expanded our understanding of the pathophysiology of the steroidogenic cells with disruption of Star. Gene expression profiles of isolated adrenal steroidogenic cells were compared between seven wild-type mice and four knockout mice lacking steroidogenic acute regulatory protein at E17.5-18.5.

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RNA-binding proteins regulate aldosterone homeostasis in human steroidogenic cells

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