Cisplatin has the advantages of strong penetration, good curative effect, wide action spectrum and synergistic effect with a variety of drugs[11]. As a consequence, it is widely used in the treatment of malignancies. Nevertheless, the nephrotoxicity of cisplatin seriously limits the clinical use of[12]. At present, the mechanism of CI-AKI is not completely clear.
1586 common differential genes were obtained from GSE106993 and GSE153625, including 817 up-regulated genes and 769 down-regulated genes. GO enrichment analysis showed that up-regulated genes were mainly related to inflammation and apoptosis. Meanwhile, oxidation-reduction processes and related molecular functions were enriched by down-regulated genes. KEGG enrichment analysis showed that TNF pathway and P53 signal pathway associated genes were up-regulated during CI-AKI. However, the genes related to metabolic pathway were down-regulated.
Inflammation is a complex biological process that runs through all stages of CI-AKI[13]. Necrotic cells induce the release of pro-inflammatory factors and chemokines, recruiting a variety of inflammatory cell infiltration, resulting in more cell death, forming a vicious circle of cell death-inflammation[14]. TNF signal pathway is an important inflammatory signal pathway, and TNF- α is the key gene of TNF signal pathway. TNF- α forms complex I with tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2 activates the transcription of nuclear factor κ B (NF- κ B). And then, NF- κ B promotes the expression of inflammation-related genes[15]. Inflammation is intimately associated with apoptosis. TNF- α not only induces inflammation, but also activates death receptor pathway and promotes apoptosis[16]. Some studies have shown that P53 signal pathway is involved in the process of apoptosis induced by TNF- α[17]. P53 can activate mitochondrial apoptosis pathway and induce cell apoptosis by changing the permeability of mitochondrial[18]. Mitochondria is not only the source of energy for eukaryotes, but also participates in the regulation of various functions of organism. We enriched a number of mitochondrial-related biological processes, cellular components and molecular functions in the down-regulated genes, which suggested that there is mitochondrial dysfunction in the process of CI-AKI. Mitochondrial dysfunction increases ROS production which aggravates mitochondrial dysfunction and releases large amounts of cytokines which induce inflammatory responses[19]. Therefore, inflammation, apoptosis and mitochondrial dysfunction play important roles in development of CI-AKI. Meanwhile, there are cross-talks between inflammation, apoptosis, and mitochondrial dysfunction.
8 hub genes were obtained through PPI network. Previous studies have shown that human homologous genes of 8 hub genes play important roles in the process of CI-AKI. It was found that the expression of P53 was up-regulated in the early stage of CI-AKI, and inhibition of P53 could improve the symptoms of CI-AKI[20]. P53 participates in the process of CI-AKI through a variety of forms. On the one hand, it regulates various ways of cell death, such as apoptosis, necrosis, iron death, etc., on the other hand, it affects the process of autophagy[18, 21–23]. STAT3 is an important Inflammation gene, which can regulate the release of inflammatory mediators and participate in inflammatory response, but also induce cell apoptosis through mitochondrial pathway[24, 25]. Inhibiting the expression of STAT3 can significantly improve the apoptosis and inflammatory response induced by cisplatin and sepsis[26, 27]. C-Jun is an important component of nuclear transcriptional activation protein, which can regulate the expression of death and inflammation-related genes[28, 29]. C-Jun is activated in a variety of kidney diseases, inhibition of C-Jun activation can improve kidney inflammatory response[30]. Caspase3 is the ultimate executor of apoptosis, which is regulated by many apoptotic pathways, such as TNF pathway and P53 pathway [16, 18]. Cadherin 1 (CDH1) is a member of the cadherin family and encodes E-cadherin, which is an important marker of epithelial-mesenchymal transformation. Studies have shown that E-cadherin is down-expressed in tubular cells with acute kidney injury, and up-regulation of E-cadherin can alleviate the inflammatory response and apoptosis in the process of CI-AKI [31]. Interestingly, it was found that CDH1 is up-regulated in CI-AKI, so what is the significance of CDH1 up-regulation? The latest study found that E-cadherin can not only regulate cell adhesion, migration and proliferation, but also limit apoptosis induced by ROS and improve cell viability [32]. This suggests that the up-regulation of CDH1 in the early stage of CI-AKI may have a protective effect on the kidney. EGF is a cytokine with multiple functions, which can bind to EGF receptors, activate downstream pathways, and regulate cell proliferation, apoptosis and differentiation[33]. Studies have shown that the expression of EGF is low in tubular cells after ischemia-reperfusion injury, and exogenous EGF contributes to the recovery of kidney function [34, 35]. However, the decrease of EGF is not linear. In CI-AKI model, it was found that the expression of EGF decreased at first, then increased, and finally decreased, suggesting that our body may repair itself by up-regulating EGF[36]. PTGS2, also known as COX-2, is an important mediator in the inflammatory process, which mediates a variety of inflammatory responses by promoting the expression of IL-6 through the regulation of prostaglandin E2 synthesis[37, 38]. Selective COX-2 inhibitors can reduce the injury of glomeruli and tubule, thereby alleviating the progression of acute kidney injury [39, 40]. CAT is an important member of the antioxidant system, which can break down hydrogen peroxide into water and carbon dioxide. The expression of CAT is low in CI-AKI model. In addition, up-regulation of CAT can protect kidney function [41].
MiRNA is a kind of non-coding RNA (19-25 nucleotide length) that regulates gene expression after transcription[42]. It is involved in many biological processes of acute kidney injury. In addition, it has been found that miR-449 is highly expressed in CI-AKI, and abnormal expression of miR-449 regulates apoptosis of kidney tubular epithelial cells through deacetylase 1/P53/Bcl2 associated X protein pathway[43]. The synthetic miR-500a-3p liposome could significantly reduce kidney injury[44]. The expression of miRNA is regulated in many ways, of which transcriptional regulation is the most common. P53-induced miR-199a-3p decreased the expression and phosphorylation of rapamycin and promoted apoptosis of kidney tubular epithelial cells[45]. In the study, we obtained several differentially expressed miRNA in the process of CI-AKI, and constructed TF/microRNA/mRNA regulatory networks, including 2 TFs, 4 miRNAs and 214 mRNAs, revealing the potential regulatory network in the process of CI-AKI.
Traditional Chinese medicine has been paid more and more attention, and the effect of traditional Chinese medicine in the treatment of acute kidney injury has been widely recognized in recent years. Zhi Bai Di Huang Wan can reduce the apoptosis of tubular epithelial cells induced by gentamicin by inhibiting the activation of Caspase-3[46]. Resveratrol is a natural phenolic compound, which can reduce cisplatin-induced apoptosis of tubular epithelial cells by activating deacetylase 1 and deacetylating P53. We screened two traditional Chinese medicines, Sang-Ye and Ban-Xia, by targeting key genes. Sang-Ye is the dry leaf of mulberry, which has the effects of reducing lipid and anti-inflammation. Flavonoids from Sang-Ye can alleviate acute kidney injury induced by high uric acid[47]. The alkaloids extracted from Sang-Ye can reduce the production of ROS and reduce the acute kidney injury induced by oxidative stress[48]. Ban-Xia, which belongs to the Araceae family, is a valuable medical plant. Banxia Baishu Tianma Decoction regulates oxidative stress in hypertensive kidney injury by up-regulating the expression of Cu-Zn superoxide dismutase and catalase 2[49].