Abstract / Summary
Abstract Although excessive dietary sodium intake is a well-recognized risk factor for hypertension, accumulating evidence indicates that it leads to broader metabolic consequences. Here, we investigated the renal and skeletal consequences of high salt loading and the protective effects of esaxerenone, a selective nonsteroidal mineralocorticoid receptor (MR) antagonist. Male Sprague-Dawley rats were infused with aldosterone and fed an 8% sodium chloride diet for 4 weeks (Aldo-HS), with or without esaxerenone. Trabecular bone architecture was assessed by micro-computed tomography, three-dimensional morphometry, and histomorphometry. Kidney and bone transcriptomes were analyzed using RNA sequencing and weighted gene co-expression network analysis. Aldo-HS rats developed marked renal calcium wasting without changes in serum calcium, phosphate, parathyroid hormone, or fibroblast growth factor 23 levels. Fractional calcium excretion was strongly inversely correlated with trabecular bone volume ( r = –0.74, p < 0.001). Aldosterone–salt loading induced substantial trabecular bone loss, which was prevented by esaxerenone. Bone transcriptomic analysis demonstrated suppression of extracellular matrix gene programs; a collagen-enriched gene module (including Col1a1 , Col1a2 , Col11a1 ) was tightly linked to calcium wasting ( r = –0.97, p < 0.001), partially restored by MR blockade, and overlapped with loci associated with bone mineral density in human genome-wide association studies. Aldosterone–salt loading induces trabecular bone loss accompanied by imbalance in bone remodeling and renal calcium wasting. MR blockade preserves skeletal integrity, supporting a modifiable bone–kidney axis and providing translational insight into skeletal complications of mineralocorticoid excess.