Abstract Body: Hypertension is a global health burden, affecting nearly one-third of adults and contributing to cardiovascular disease, kidney failure, and death. Chronic hypertension causes progressive multi-organ damage, yet the molecular mechanisms remain poorly understood. To address this critical gap, we generated a time-resolved multi-organ transcriptomic atlas using the Dahl salt-sensitive (SS) rat, a well-characterized and broadly used rodent model of hypertension. This comprehensive atlas focused on capturing dynamic molecular changes in the kidney cortex and medulla, heart, and liver.
Male SS rats (9-11 weeks old) were fed either a high-salt diet (4.0% NaCl; HS) to induce hypertension or a normal salt diet (0.4% NaCl) and were euthanized on days 7, 14, 21, and 35 of HS. RNA sequencing was performed on kidney cortex and medulla, heart, and liver (n=6 per group), generating high-resolution data to capture organ-specific and time-dependent changes in gene expression. Complementary histological and biochemical analyses were conducted to assess salt-induced tissue injury and physiological alterations.
Our analysis revealed temporal, organ-specific transcriptional trajectories in response to salt-induced hypertension. The kidney medulla showed significant early activation (adj p<0.05) of inflammatory pathways, including interferon-γ, interferon-α, and IL-6/JAK/STAT3 signaling by day 7. In contrast, the cortex showed delayed activation of TNF-α signaling by day 21. Oxidative metabolism demonstrated distinct patterns with a transient increase in the cortex on day 7, followed by decline, and early sustained reduction in the medulla. The heart and liver also showed unique transcriptional responses, especially in inflammatory and metabolic pathways. Notably, E2F transcription factor target genes involved in cell cycle regulation were consistently upregulated (adj p<0.05) in all three organs, indicating a shared response. Furthermore, the analysis identified druggable targets, highlighting potential to new therapies or repurposing existing drugs to mitigate hypertension-induced organ damage. Histological and biochemical findings (n=6, p <0.05) corroborated the gene expression changes and highlighted progressive, organ- and region-specific tissue injury.
In conclusion, this integrative approach provides a detailed molecular landscape to understand hypertension-induced multi-organ damage and serves as a resource for identifying new pathways and therapeutic targets.