High-dose dexamethasone injection disordered metabolism and multiple protein kinases expression in the mouse kidney.

Zaikuan Zhang,Yingchun Ran,Lei Xu,Yajun Xie,Zheng Pan

doi:10.1042/bsr20211847

Abstract

Glucocorticoids (GCs) have been widely used in clinical treatment as anti-inflammatory, anti-shock and immunosuppressive medicines. However, the effect of excessive GCs on immune response and metabolism of kidney remains unclear. Here, we profiled the gene expression of kidney from mice with high-dose dexamethasone (DEX) treatment. A total of 1193 differentially expressed genes (DEGs) were screened in DEX treatment group compared with the saline group, including 715 down- regulated and 478 up-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of these DEGs showed extracellular matrix (ECM)–receptor interaction, cell adhesion molecules signaling pathway were significantly enriched, and that the vast majority of DEGs were involved in monocarboxylic acid metabolism, leukocyte cell–cell adhesion and fatty acid metabolism. Gene set enrichment analysis (GSEA) revealed that DEGs were strongly associated with immune-response and cell adhesion gene sets, such as Fc γ R-mediated phagocytosis, leukocyte transendothelial migration, T-cell receptor signaling pathway, cell adhesion, ECM–receptor interaction and focal adhesion-associated pathways. KEGG pathway analysis of differentially expressed kinases (DEKs) showed T-cell receptor and forkhead box class O signaling pathway were enriched. Furthermore, we found multiple protein kinases expression were dysregulated greatly after dexamethasone treatment, including classical effector of GCs stimulation-serum and GC-regulated kinase. These protein kinases are involved in multiple signaling pathways in mice kidney, such as mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We profiled the gene expression of the kidney from high-dose dexamethasone-treated mice and provided important information for further study the mechanism of side effects of GCs in clinical therapy.

Highlights

Glucocorticoids (GCs), a key regulatory hormone in the human body and functioning in homeostasis and development [1], are widely used in clinical treatment as an anti-inflammatory, anti-shock and immunosuppressive agent [2,3]
DEX treatment affected the expression of genes involved in metabolism, inflammation and immune response
Our data showed that lipid metabolism-associated genes, such as leptin (Lep), apolipoprotein c3 (Apoc3), apolipoprotein H (Apoh), odorant-binding protein 2a (Obp2a), apolipoprotein a4 (Apoa4), SEC14-like lipid binding 4 (Sec14l4) and cytochrome P450 family 2 subfamily B member 10 (Cyp2b10) were up-regulated, whereas prolactin receptor (Prlr), reducing the speed limit enzyme stearyl coenzyme A desaturation enzyme 1 in the biosynthesis of monounsaturated fatty acids, was down-regulated after DEX treatment (Figure 1B), indicating that long-term and high-dose GCs induced lipid metabolism disorders

Summary

Introduction

Glucocorticoids (GCs), a key regulatory hormone in the human body and functioning in homeostasis and development [1], are widely used in clinical treatment as an anti-inflammatory, anti-shock and immunosuppressive agent [2,3]. Given its anti-inflammatory cytokine property, GCs have become the most frequently prescribed drugs in autoimmune, inflammatory and allergic diseases, such as rheumatology [4], septic shock [5], inflammatory bowel disease [6] and so on. Low doses of GCs are clinically recommended for the treatment of septic shock [7] and rheumatic diseases [8]. Owing to a series of deleterious side effects that may occur after long-term or high-dose usage of GCs, such as osteoporosis, hyperglycemia, insulin resistance, License 4.0 (CC BY). A complete understanding of side effects and pathogenic mechanisms of long-term and high-dose treatment is essential to determine the appropriate use of these drugs

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Discussion

Conclusion