EGR1 regulates oxidative stress and aldosterone production in adrenal cells and aldosterone-producing adenomas

Abstract

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism, a common form of endocrine hypertension. Here, we demonstrate that Early Growth Response 1 (EGR1) plays a dual role in adrenal cell biology, regulating both oxidative stress and aldosterone production. Using RNA sequencing of RSL3-treated human adrenal cells and spatial transcriptomics of adrenal glands from patients with primary aldosteronism, we identify EGR1 as a key gene associated with RSL3-related oxidative stress and APAs. We show that EGR1 silencing decreases oxidative stress and increases CYP11B2 gene expression and aldosterone production in adrenal cells, while its overexpression has the opposite effects. Notably, EGR1 expression is downregulated in APAs and aldosterone-producing micronodules compared to the adjacent adrenal cortex, which correlates in part with decreased levels of oxidative stress markers. The adrenal cortex of pigs with secondary hyperaldosteronism shows decreased immunostaining of EGR1 and a marker of oxidative stress, suggesting a potential link between EGR1 expression, oxidative stress levels, and adrenocortical function. These findings reveal a novel mechanism linking EGR1 to oxidative stress regulation and aldosterone production in adrenal cells, with potential implications for the pathogenesis of APAs and other adrenocortical tumors. • EGR1 mediates RSL3-related oxidative stress in adrenocortical cells and adenomas. • RSL3 inhibits CYP11B2 expression and aldosterone synthesis. • Aldosterone-producing micronodules and adenomas show reduced EGR1 expression. • EGR1 knockdown decreases oxidative stress and enhances aldosterone production. • EGR1 plays a dual role in promoting oxidative stress and aldosterone suppression in adrenal cells.

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