Sexually dimorphic interzonal crosstalk reshapes the adrenal cortex in response to pathophysiological challenges

Structured Abstract Background Primary aldosteronism is the most common form of secondary arterial hypertension, due to autonomous aldosterone production from the adrenal cortex. Genome wide association studies discovered genetic risk loci associated with the disease, which may affect adrenal cortex renewal, differentiation and lineage conversion. Genetic susceptibility may be modulated by environmental challenges. Method Here we investigate how environmental cues affecting mineralocorticoid output modulate adrenal cortex homeostasis, cell lineage conversion and zone-specific transcriptional landscape. We have used a newly developed Cyp11b2 Cre mouse model and characterised its adaptation to a high or low salt diet (HSD, LSD ) , as well as dexamethasone (DEX) treatment. To explore underlying mechanisms, deep functional and morphological phenotyping, lineage tracing and spatial transcriptomics of the adrenal cortex were performed. Results Cyp11b2 expression was detected in Cyp11b2 Cre - m T m G mice as early as day P1 in different areas of the ZG, associated with high plasma aldosterone levels, with lineage conversion of zona glomerulosa (ZG) into zona fasciculata (ZF) cells progressing between 2 and 9 weeks of age and a progressive reduction of ZG size and evolution of cell components of the adrenal cortex over time. Transdifferentiation progressed into the X-zone (ZX) in females, revealing a previously unrecognized connection between ZF and ZX cells in adult mice. A sexually dimorphic, reciprocal interaction between the ZG and the ZF in adapting to salt diets or DEX treatment was observed, involving changes in cell composition and transcriptional reprogramming of the three zones. Conclusion HSD, LSD and DEX induce a sexually dimorphic cellular and transcriptional response, involving all layers of the adrenal cortex, and the reciprocal contribution of ZG and ZF cells, indicating functional interaction between adrenocortical zones in adapting to external cues.