Cell Type Specific Sex Differences in Salt-sensitive Hypertension and End-organ Damage Revealed by Single-nucleus RNA-seq

Sex differences in hypertension are clinically significant, yet a systemic understanding of the molecular and cellular mechanisms underlying these differences, including their impact on end-organ damage, remains lacking. Here we focused on salt-sensitive hypertension, a highly modifiable risk factor, and performed single-nucleus RNA-seq on kidney and cardiac left ventricle (LV) tissue samples from male and female Dahl salt sensitive rats exposed to a high-salt diet for 3 days and 21 days. Our findings revealed male-biased cellular changes, including a higher proportion of injured proximal tubule (PT) cells in the kidney and increased immune cell infiltration in both the kidney and LV, consistent with more severe tissue injury observed in males. Molecular analysis showed an expansion in the number of sex-biased genes following the high-salt diet, particularly in injured PTs, endothelial cells, and vascular smooth muscle cells (VSMCs) in the kidney, as well as fibroblasts in the LV. We further identified sex-specific hypertension-related genes, such as the male-specific upregulation of the vascular fibrosis-associated gene Smad3 in kidney VSMCs, and the higher abundance of the calcification inhibitor Mgp in female LV fibroblasts. Notably, in kidney PTs and LV fibroblasts, sex differences in differentially expressed genes (DEGs) induced by the high-salt diet significantly overlapped with androgen-responsive genes, with male-abundant DEGs aligning with androgen-upregulated expression patterns and female-abundant DEGs with androgen-downregulated patterns. This study highlights cell type-specific, sex-dependent responses to salt and hypertension, including both reported and additional sex-related differences in gene expression, providing a valuable resource for decoding molecular mechanisms of sex differences in blood pressure regulation and end-organ damage. National Institutes of Health grant HL149620, DK129964, and HL121233. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.