Transcriptomic Analysis Revealed an Important Role of Peroxisome-Proliferator-Activated Receptor Alpha Signaling in Src Homology Region 2 Domain-Containing Phosphatase-1 Insufficiency Leading to the Development of Renal Ischemia-Reperfusion Injury
FRONTIERS IN MEDICINE(2022)
Abstract
In kidney transplantation, the donor kidney inevitably undergoes ischemia-reperfusion injury (IRI). It is of great importance to study the pathogenesis of IRI and find effective measures to attenuate acute injury of renal tubules after ischemia-reperfusion. Our previous study found that Src homology region 2 domain-containing phosphatase-1 (SHP-1) insufficiency aggravates renal IRI. In this study, we systematically analyzed differences in the expression profiles of SHP-1 (encoded by Ptpn6)-insufficient mice and wild-type mice by RNA-seq. We found that a total of 161 genes showed at least a twofold change, with a false discovery rate < 0.05 in Ptpn6 (+/mev) mice after IRI and 42 genes showing more than a fourfold change. Of the eight genes encoding proteins with immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that bind to Ptpn6, three were upregulated, and five were downregulated. We found that for the differentially expressed genes (DEGs) with a fold change > 2, the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were the cell division pathway and peroxisome-proliferator activated receptor PPAR alpha signaling pathways. Furthermore, the downregulated genes of the PPAR alpha signaling pathway were mainly related to fatty acid absorption and degradation. Using an agonist of the PPAR alpha signaling pathway, fenofibrate, we found that renal IRI was significantly attenuated in Ptpn6 (+/mev) mice. In summary, our results show that insufficiency of SHP-1 inhibits the expression of genes in the PPAR alpha signaling pathway, thereby leading to increased reactive oxygen species (ROS) and exacerbating the renal IRI. The PPAR alpha signaling agonist fenofibrate partially attenuates renal IRI induced by SHP-1 insufficiency.
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Key words
kidney transplantation, renal ischemia-reperfusion injury, SHP-1, PPAR alpha signaling, bioinformatics
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