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

Aldosterone-producing cell clusters (APCCs), which share some transcriptomic features with aldosterone-producing adenomas, are frequently observed in the adrenal cortex of aged individuals and those with primary aldosteronism. However, the mechanisms driving APCC formation remain poorly understood.

We performed an integrated analysis using spatial transcriptomics and single-cell RNA sequencing of APCC cells, aldosterone-producing adenoma cells, and zona glomerulosa (ZG) cells present in the same adrenal gland of a patient with unilateral primary aldosteronism, with validation analyses conducted on tissue samples from 2 additional patients.

APCC cells exhibited a distinct cellular population with a gene expression profile more similar to that of the ZG cells than that of aldosterone-producing adenoma cells. In silico perturbation and in vitro studies suggest that the stress-responsive transcription factor NR4A2 (Nuclear receptor subfamily 4 group A member 2) is activated in ZG cells in response to a variety of stresses, such as adrenocorticotropic hormone stimulation, thereby promoting the progression from ZG to APCC cells.

Our findings suggest that NR4A2 activation in ZG cells functions as a key molecular mediator in stress-induced APCC formation at least in some cases. Some APCCs maintained ZG-like characteristics with heightened stress responsiveness, representing a distinct cellular state from aldosterone-producing adenomas, which exhibit metabolic reprogramming and enhanced energy metabolism.