Integrated Analysis of m6A Methylome in Cisplatin-Induced Acute Kidney Injury and Berberine Alleviation in Mouse

Abstract

BackgroundN6-methyladenosine (m6A) is the most abundant modification known in mRNAs. It participates in a variety of physiological and pathological processes, such as metabolism, inflammation, and apoptosis.AimsTo explore the mechanism of m6A in cisplatin-induced acute kidney injury (AKI) and berberine alleviation in mouse.MethodsThis study investigated the N6-methyladenosine (m6A) methylome of kidneys from three mouse groups: C57 mice (controls), those with CI-AKI (injury group, IG), and those pretreated with berberine (treatment group, TG). Methylated RNA Immunoprecipitation Next Generation Sequencing (MeRIP-seq) and RNA-seq were performed to identify the differences between the injury group and the control group (IvC) and between the treatment group and the injury group (TvI). Western blotting was performed to identify the protein levels of candidate genes.ResultsIn IvC, differentially methylated genes (DMGs) were enriched in metabolic processes and cell death. In TvI, DMGs were enriched in tissue development. Several genes involved in important pathways related to CI-AKI showed opposite methylation and expression trends in the IvC and TvI comparisons.Conclusionm6A plays an important role in cisplatin induced AKI and berberine may alleviate this process.

Alteration of N6-Methyladenosine RNA Profiles in Cisplatin-Induced Acute Kidney Injury in Mice

“…We further revealed that the expression patterns of m 6 A-modified RNAs changed significantly in response to cisplatin. Similar to our results, a recent study also found differences in the expression profile of m 6 A methylation in the kidney tissues after cisplatin treatment (Shen J. et al, 2020). The parent genes of the differentially expressed m 6 A methylated mRNAs, such as Krt20, Ccdc85b, and Serpina3n were found to be upregulated in both studies, while Ctnna2, Afm, Pzp, and Dgkg were downregulated.…”

“…This study highlights an unappreciated systemic role of renal glucose metabolism in kidney damage (Legouis et al, 2020). In cisplatin-induced AKI, a recent study indicated that genes with differently altered methylation of m 6 A sites were highly enriched in metabolic processes (Shen J. et al, 2020). Regarding amino acid metabolism, the levels of phenylalanine, allantoic acid, methylcysteine, gamma-aminobutyric acid, beta-alanine, and aminoadipic acid in the renal cortex of Sprague Dawley rats were increased significantly after intraperitoneal injection of endotoxin lipopolysaccharide (LPS) (Ping et al, 2019).…”

“…In addition, further analysis demonstrated that the parent genes of the top three altered methylated mRNAs (Fosl1, Krt20, and Cdkn1a) participated in regulating apoptotic pathways (Torgovnick et al, 2018;. A study conducted by Shen J et al also found that genes with elevated methylation of m 6 A sites were significantly enriched in the cell death processes, such as apoptotic processes (Shen J. et al, 2020). Since apoptosis in renal tubular epithelial cells is a major feature of AKI, we would predict that m 6 A methylation has a pivotal role in tubular cell death.…”

Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury

“…In an I/R AKI mouse model, transcriptome sequencing of renal tubules suggested that metabolic maladaptation was implicated in AKI progression to chronic fibrosis, with massive lipid droplet accumulations observed in renal tubular epithelial cells ( Zhang et al, 2018 ). In cisplatin-induced acute kidney injury, methylated RNA immunoprecipitation sequencing and RNA sequencing revealed that metabolic processes and cell death were activated in the injury group ( Shen et al, 2020 ). In mouse sepsis-associated AKI, the differentially expressed genes (DEGs) from three paired tissues’ RNA-seq were enriched in the nod-like receptor signaling, toll-like receptor signaling, and JAK/STAT signaling pathways ( Yang et al, 2020 ).…”

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

“…The general mechanisms of these natural products are summarized in Figure 5 . These include blockage of cisplatin renal uptake and transportation [ 22 ], inhibition of oxidative stress [ 96 , 97 ], inhibition of inflammation [ 98 , 99 ], inhibition of P53 signaling pathways [ 52 ], inhibition of mitogen-activated protein kinases [ 100 ], attenuation of cell death, and enhancement of cellular antioxidant defense systems such as SOD, catalase, and the Nrf2 pathway [ 101 , 102 ]. Autophagy and mitophagy are also involved in cisplatin-induced kidney injury [ 51 , 103 ] and can be modulated by natural products for protective purposes [ 104 , 105 , 106 , 107 ].…”