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Transcriptomic profiling of LPS-induced adrenal inflammation in sorted adrenal endothelial cells from C576L6 mice

ABSTRACT: Altogether, this is the first study presenting the global changes of the transcriptome in the adrenal microvascular cells. The results of RNA sequencing and subsequent bioinformatics analysis revealed that adrenal vascular endothelial cells are active players not only involved in maintenance of the adrenal gland microenvironment, but also they play a key role in pathogen recognition and initiation of inflammation. However, our results also strongly suggest that systemic administration of LPS, which recapitulates to some degree situation in people with meningococcal sepsis, may develop certain damage, including vascular inflammation, hypoxia, blood coagulation and leakage. That may contribute to the adrenal dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE139134 | GEO | 2020/01/09

REPOSITORIES: GEO

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Project description:# Background Acute kidney injury (AKI) in sepsis patients increases patient mortality. Endothelial cells are important players in the pathophysiology of sepsis-associated AKI (SA-AKI), yet knowledge regarding their spatiotemporal involvement in coagulation disbalance and leukocyte recruitment is lacking. This study investigated the identity and kinetics of responses of different microvascular compartments in kidney cortex in response to SA-AKI. # Methods Laser microdissected arterioles, glomeruli, peritubular capillaries, and postcapillary venules from kidneys of mice subjected to cecal ligation and puncture (CLP) were analyzed using RNA sequencing. Differential expression and pathway enrichment analyses identified genes involved in coagulation and inflammation. A selection of these genes was evaluated by RT-qPCR in microvascular compartments of renal biopsies from patients with SA-AKI. The role of two identified genes in lipopolysaccharide-induced endothelial coagulation and inflammatory activation were determined in vitro in HUVEC using siRNA-based gene silencing. # Results CLP-sepsis in mice induced altered expression of approximately 400 genes in the renal microvasculature, with microvascular compartments exhibiting unique spatiotemporal responses. In mice, changes in gene expression related to coagulation and inflammation were most extensive in glomeruli at early and intermediate time points, with high induction of Plat, Serpine1, Thbd, Icam1, Stat3, and Ifitm3. In human SA-AKI, PROCR and STAT3 were induced in postcapillary venules, while SERPINE1 expression was diminished. IFITM3 was increased in arterioles and glomeruli. In vitro studies revealed that STAT3 and IFITM3 partly control endothelial coagulation and inflammatory activation. # Conclusion Renal microvascular compartments in mice and humans exhibited heterogeneous changes in coagulation- and inflammation-related gene expression in response to SA-AKI. Additional research should aim at understanding the functional consequences of the here described heterogeneous microvascular responses to establish the usefulness of identified genes as therapeutic targets in SA-AKI.

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Transcriptomic profiling of LPS-induced adrenal inflammation in sorted adrenal endothelial cells from C576L6 mice

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