The Spatially Resolved Kidney Transcriptome Signatures in Rat Models of Trauma-Induced Acute Kidney Injury

Using bulk and spatial transcriptomics in rat model, we defined early responses to hemorrhagic shock, rhabdomyolysis, and their combination. Rhabdomyolysis was the primary driver of transcriptional changes, while hemorrhagic shock, rhabdomyolysis, and their combination produced synergistic and lethal response with distinct regional and molecular signatures. We identified central mechanisms linking trauma to tubular injury and AKI progression.

Trauma is a leading global cause of death, and AKI significantly worsens outcomes. Hemorrhagic shock (HS) and rhabdomyolysis (RM) are major contributors, yet their individual and combined effects on the kidney remain poorly defined.

Using a clinically relevant rat model that closely mimics human trauma, we performed bulk and spatial transcriptomics to characterize early renal responses to HS, RM, and their combination (RM-HS). Commercial mouse spatial transcriptomics probes were successfully applied to rat kidney tissue, enabling cost-effective and region-specific gene expression profiling.

RM emerged as the dominant driver of transcriptional changes, while RM-HS triggered a synergistic, mortality-associated response. Comparative analyses revealed distinct regional and molecular signatures; HS suppressed metabolic activity, whereas RM induced widespread upregulation of inflammatory and stress-response pathways.

We propose a mechanistic framework linking these traumatic insults to tubular cell injury and death, with mitochondrial dysfunction, dysregulated lipid metabolism, Perilipin 2 expression, and ferroptosis as central components. This integrative model advances our understanding of trauma-induced renal injury and may enable the identification of novel biomarkers and therapeutic strategies to mitigate AKI severity in patients with trauma.