Differential expression of the Nrf2-linked genes in pediatric septic shock

Abstract

Introduction: Experimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress. Prior analysis of a pediatric septic shock transcriptomic database showed that the Nrf2 response is a top 5 upregulated signaling pathway in early pediatric septic shock.

Methods: We conducted a focused analysis of 267 Nrf2-linked genes using a multicenter, genome-wide expression database of 180 children with septic shock 10 years of age or younger and 53 healthy controls. The analysis involved RNA isolated from whole blood within 24 h of pediatric intensive care unit admission for septic shock and a false discovery rate of 5 %. We compared differentially expressed genes from (1) patients with septic shock and healthy controls and (2) across validated gene expression-based subclasses of pediatric septic shock (endotypes A and B) using several bioinformatic methods.

Results: We found upregulation of 123 Nrf2-linked genes in children with septic shock. The top gene network represented by these genes contained primarily enzymes with oxidoreductase activity involved in cellular lipid metabolism that were highly connected to the peroxisome proliferator activated receptor and the retinoic acid receptor families. Endotype A, which had higher organ failure burden and mortality, exhibited a greater downregulation of Nrf2-linked genes than endotype B, with 92 genes differentially regulated between endotypes.

Conclusions: Our findings indicate that Nrf2-linked genes may contribute to alterations in oxidative signaling and intermediary metabolism in pediatric septic shock.

Fig. 1

Differentially regulated genes corresponding to a gene network having peroxisome proliferator-activated receptor-α (PPARA)-related and retinoic acid receptor-α (RXRA) genes as highly connected nodes. The degree of green intensity in a gene node corresponds to decreased expression, and the degree of red intensity in a given gene node corresponds to increased expression in the subjects with septic shock, relative to controls, respectively. The list of network genes is provided in Additional file 3: Table S3. HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A synthase

Fig. 2

Gene Expression Dynamics Inspector–generated mosaics of differentially expressed mitochondrial genes for the two previously defined septic shock endotypes. The 138 gene probes, corresponding to 92 unique genes, are depicted along the same coordinates across the two expression mosaics. Red intensity correlates with increased gene expression, and blue intensity correlates with decreased gene expression. Clear differences in color patterns illustrate differential expression of Nrf2-regulated genes across patient endotypes A and B, with general downregulation in endotype A. Endotype A subjects have higher illness severity, higher mortality, and higher organ failure burden than endotype B subjects

Fig. 3

Differentially regulated genes corresponding to a gene network using glutathione to respond to oxidative stress as highly connected nodes. The degree of green intensity in a gene node corresponds to decreased expression, and the degree of red intensity in a given gene node corresponds to increased expression in the endotype A subjects with septic shock, relative to the endotype B subjects with septic shock, respectively. The list of network genes is provided in Additional file 5: Table S5

Fig. 4

Differentially regulated genes corresponding to a gene network using superoxide-generating nicotinamide adenine dinucleotide phosphate hydrate (NADPH) oxidase activity to respond to reactive oxygen species as highly connected nodes. The degree of green intensity in a gene node corresponds to decreased expression, and the degree of red intensity in a given gene node corresponds to increased expression in the endotype A subjects with septic shock, relative to the endotype B subjects with septic shock, respectively. The list of network genes is provided in Additional file 6: Table S6. PI3K phosphatidylinositide 3-kinase