Molecular and Structural Changes in Bone Under Aldosterone-Salt Hypertension Uncovered by Transcriptome-Wide Profiling

Background: Recent clinical studies have suggested a potential link between primary aldosteronism and impaired bone metabolism; however, the mechanistic basis and underlying pathways remain unclear. To investigate this connection, we utilized a rat model of aldosterone and salt loading and examined bone structural and molecular changes. Methods: Male Sprague-Dawley rats were infused with aldosterone and provided 8% NaCl diet for 4 weeks (Aldo+HS group). A treatment group received esaxerenone mixed in a chow (0.03%) in addition to aldosterone and salt (Esax group). Control rats received vehicle. At 4 weeks, femurs were collected and trabecular bone in the distal femoral metaphysis was analyzed by histomorphometry. Transcriptome analysis was performed using RNA extracted from bone tissue. Results: The Aldo+HS group exhibited elevated blood pressure without overt histological changes in the kidney, suggesting early-stage renal impairment. Serum calcium levels remained unchanged; however, the Aldo+HS group showed significantly increased fractional excretion of calcium (FECa), accompanied by marked reductions in trabecular bone volume (BV/TV). FECa was strongly negatively correlated with BV/TV (r = –0.87, p < 0.01). Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels were not altered among three groups, indicating that bone loss occurred in the absence of overt CKD-related mineral imbalance. Weighted gene co-expression network analysis (WGCNA) of bone transcriptome data identified a gene module enriched for extracellular matrix components (e.g., Col1a1, Col5a1, Bgn), whose eigengene expression was also strongly negatively correlated with FECa (r = –0.97, p < 0.01). Esaxerenone treatment normalized FECa, preserved trabecular bone structure, and restored the expression profile of the identified gene module. Conclusion: Aldosterone and salt loading induced early bone metabolic alterations through mechanisms independent of reduced glomerular filtration. These changes were associated with disrupted bone matrix gene regulation and were effectively prevented by mineralocorticoid receptor blockade. Our findings highlight a novel bone–kidney axis and support esaxerenone as a potential therapeutic agent for aldosterone-salt–induced osteopathy.