Role of Stress-Responsive NR4A2 in Aldosterone-Producing Cell Cluster Formation

Area of Science:

• Endocrinology
• Molecular Biology
• Genomics

Background:

• Aldosterone-producing cell clusters (APCCs) are found in the adrenal cortex of aging individuals and those with primary aldosteronism.
• APCCs share transcriptomic similarities with aldosterone-producing adenomas.
• The mechanisms driving APCC formation are not well understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying APCC formation.
• To compare the transcriptomic profiles of APCC cells, aldosterone-producing adenoma cells, and zona glomerulosa (ZG) cells.

Main Methods:

• Integrated analysis using spatial transcriptomics and single-cell RNA sequencing.
• Analysis performed on adrenal gland tissue from a patient with unilateral primary aldosteronism.
• Validation studies conducted on tissue samples from two additional patients.

Main Results:

• APCC cells displayed a gene expression profile closer to ZG cells than to aldosterone-producing adenoma cells.
• In silico and in vitro studies indicated that the stress-responsive transcription factor NR4A2 is activated in ZG cells.
• Activated NR4A2 promotes the transition from ZG cells to APCC cells, particularly under stress conditions like ACTH stimulation.

Conclusions:

• NR4A2 activation in ZG cells is a key mediator in stress-induced APCC formation.
• Some APCCs retain ZG-like features and heightened stress responsiveness, differentiating them from aldosterone-producing adenomas.
• Aldosterone-producing adenomas are characterized by metabolic reprogramming and increased energy metabolism.