Uncovering molecular markers of the microvascular endothelial response in sepsis-associated acute kidney injury: a translational study in mice and humans

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INTRODUCTION: Endothelial cells play a central role in the pathophysiology of sepsis-associated acute kidney injury (SA-AKI), yet we have limited understanding of the markers of microvascular-specific response. We therefore employed a translational approach integrating spatially resolved transcriptomics in a mouse SA-AKI model with validation in human kidney tissues and plasma, aiming to define the molecular signature of the endothelial response to SA-AKI in mice and in human patients. METHODS: In this post hoc analysis of prospectively collected data, we identified sepsis-associated target mRNAs and validated their expression via RT-qPCR in distinct renal microvascular compartments isolated by laser microdissection (LMD) from both cecal ligation and puncture (CLP) mice and post-mortem kidney biopsies of SA-AKI patients. Additionally, we measured the corresponding circulating proteins in plasma from two patient cohorts with sepsis and SA-AKI: one consisting of patients presenting to the emergency department, and the other of patients with severe sepsis requiring organ support in the ICU. RESULTS: We identified several differentially expressed genes in the renal microvasculature following sepsis, including Mt1, Mt2, Saa3, Hp, C3, Sparc, Mmp8, and Chil3. Whole-organ samples from CLP mice also showed increased expression in the liver and lung. Except for SPARC, all genes were similarly upregulated in human kidney biopsies from SA-AKI patients. Circulating protein levels were elevated in sepsis and SA-AKI patients compared to controls; however, only CHI3L1 and MMP8 showed significantly higher levels in SA-AKI versus sepsis across both early and advanced stages. CONCLUSION: Our findings reveal markers of the microvascular response to sepsis, which include increased levels of HP, C3, Chil3/CHI3L1, and MMP8, both at the transcriptomic level in mouse and human kidney microvasculature and at the protein level in circulating plasma of SA-AKI patients. The upregulation of these markers was shared across multiple organs and may reflect widespread endothelial activation contributing to sepsis pathophysiology.

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