Reprogramming of Iron Metabolism in Primary Aldosteronism

Background: Aldosterone influences erythrocyte physiology and oxygen handling, but whether these effects are attributable to aldosterone-mediated changes in iron metabolism is unknown. The objective of this study was to characterize the influence of aldosterone excess on the proteomic landscape of iron metabolism.

Methods: The plasma proteome (1500 proteins) of participants with overt PA (n=50) was compared to that of normotensive controls without PA (n=61). To isolate aldosterone-dependent effects, participants without overt PA underwent oral sodium suppression to quantify renin-independent aldosterone production, enabling monotonic dose-response analyses across the PA continuum (subclinical to overt PA). Differential abundance testing was performed with control for false discovery rate, and Reactome was used for pathway enrichment analysis. To assess clinical relevance, aldosterone dose-response trends with blood count parameters (hemoglobin, hematocrit, red blood cell count) were examined.

Results: 903 proteins in the peripheral circulation were differentially abundant in overt PA versus controls without PA. The most significantly increased protein in PA was CYBRD1, involved in iron reduction and absorption (logFC=1.47; P=1.36 × 10-97). Pathway enrichment identified multiple iron-related pathways, including cytoprotection and heme metabolism by HMOX1 (P < 0.001), scavenging of heme from plasma (P < 0.01), heme signaling (P=0.023) and O2/CO2 exchange in erythrocytes (P=0.040), collectively reflecting increased iron utilization and mobilization to support red blood cell production. Linear aldosterone dose-dependent trend analyses across the PA continuum identified 82 proteins paralleling disease severity. These proteins demonstrated higher abundance of hemoglobin subunits and heme biosynthesis proteins (HBA1/HBB, HMBS, UROS, HPX), with increased erythrocyte gas-exchange enzymes (BPGM, PKLR, CA1/CA3), supporting enhanced erythrocyte oxygen handling and preferential iron utilization for heme synthesis. This redirection of iron appeared to occur at the expense of mitochondrial oxidative metabolism (lower abundance of CYCS and ETFA), antioxidant buffering (lower abundance of GPX3) and increased oxidative stress signaling (higher abundance of PRDX1 and NCF1). Finally, there were dose-dependent associations between renin-independent aldosterone and hemoglobin, hematocrit, and red blood cell count.

Conclusion: PA is characterized by reprogramming of iron metabolism toward heme synthesis and erythroid expansion at the expense of mitochondrial iron pathways, yielding a measurable iron metabolic signature with heightened susceptibility to oxidative stress. These findings demonstrate alterations in iron metabolism that parallel the severity spectrum of PA, implicating the role of dysregulated iron metabolism in the pathology of PA.