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

2021 ◽  
Vol 8 ◽  
Author(s):  
Can-Ming Li ◽  
Ming Li ◽  
Wen-Bo Zhao ◽  
Zeng-Chun Ye ◽  
Hui Peng
Keyword(s):  
Acute Kidney Injury ◽  
Bioinformatics Analysis ◽  
Kidney Injury ◽  
Metabolic Process ◽  
Total Level ◽  
In Cis

Aim: To identify the alterations of N6-methyladenosine (m6A) RNA profiles in cisplatin-induced acute kidney injury (Cis-AKI) in mice.Materials and Methods: The total level of m6A and the expression of methyltransferases and demethylases in the kidneys were measured. The profiles of methylated RNAs were determined by the microarray method. Bioinformatics analysis was performed to predict the functions.Results: Global m6A levels were increased after cisplatin treatment, accompanied by the alterations of Mettl3, Mettl14, Wtap, Fto, and Alkbh5. A total of 618 mRNAs and 98 lncRNAs were significantly differentially methylated in response to cisplatin treatment. Bioinformatics analysis indicated that the methylated mRNAs predominantly acted on the metabolic process.Conclusion: M6A epitranscriptome might be significantly altered in Cis-AKI, which is potentially implicated in the development of nephrotoxicity.

scholarly journals Remote Ischemic Preconditioning Protects Cisplatin-Induced Acute Kidney Injury through the PTEN/AKT Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Wanfen Zhang ◽  
Cheng Chen ◽  
Ran Jing ◽  
Tongqiang Liu ◽  
Bicheng Liu
Keyword(s):  
Acute Kidney Injury ◽  
Ischemic Preconditioning ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Akt Signaling ◽  
Remote Ischemic Preconditioning ◽  
Pten Mrna ◽  
Induce Resistance ◽  
In Cis

Although cisplatin (Cis) is an effective chemotherapeutic agent in treatment of various cancers, its adverse effect of nephrotoxicity limits the clinical application. Remote ischemic preconditioning (RIPC) is a strategy to induce resistance in a target organ against the oxidative stress and injury by applying transient, brief episodes of ischemia. However, whether RIPC exerts protective effect on Cis-induced renal injury remains unclear. In this study, we showed that RIPC significantly alleviated the renal functional and histopathological damage of Cis-induced acute kidney injury (AKI) mice. Furthermore, RIPC substantially reversed the downregulation of miR-144 and upregulation of PTEN in renal tissues of Cis-induced AKI mice and alleviated tubular cell apoptosis via activating PTEN/AKT signaling. In mechanism, we demonstrated that miR-144 directly targets the 3’-UTR of PTEN mRNA, and then the elevation of miR-144 in RIPC activates PTEN/AKT signaling by downregulating PTEN expression to achieve its antiapoptosis effect. Collectively, our results indicate that RIPC may be a potential therapeutic strategy in Cis-induced AKI, and provide insights on the underlying molecular mechanisms of cisplatin’s nephrotoxicity.

scholarly journals Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury by Inhibiting Ferroptosis

2022 ◽  
Vol 2022 ◽  
pp. 1-14
Author(s):  
Lu Zhou ◽  
Peng Yu ◽  
Ting-ting Wang ◽  
Yi-wei Du ◽  
Yang Chen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Inhibitory Effect ◽  
Ros Generation ◽  
Molecular Events ◽  
Mda Content ◽  
Effect Of Pd ◽  
In Cis

Cisplatin is widely used in the treatment of solid tumors, but its application is greatly limited due to its nephrotoxicity; thus, there is still no effective medicine for the treatment of cisplatin-induced acute kidney injury (Cis-AKI). We previously identified that polydatin (PD) exerts nephroprotective effects by antioxidative stress in AKI models. Recent evidence suggests that oxidative stress-induced molecular events overlap with the process of ferroptosis and that there are common molecular targets, such as glutathione (GSH) depletion and lipid peroxidation. Nevertheless, whether the nephroprotective effect of PD is related to anti-ferroptosis remains unclear. In this study, the inhibitory effect of PD on ferroptosis was observed in both cisplatin-treated HK-2 cells (20 μM) in vitro and a Cis-AKI mouse model (20 mg/kg, intraperitoneally) in vivo, characterized by the reversion of excessive intracellular free iron accumulation and reactive oxygen species (ROS) generation, a decrease in malondialdehyde (MDA) content and GSH depletion, and an increase in glutathione peroxidase-4 (GPx4) activity. Remarkably, PD dose-dependently alleviated cell death induced by the system Xc− inhibitor erastin (10 μM), and the effect of the 40 μM dose of PD was more obvious than that of ferrostatin-1 (1 μM) and deferoxamine (DFO, 100 μM), classical ferroptosis inhibitors. Our results provide insight into nephroprotection with PD in Cis-AKI by inhibiting ferroptosis via maintenance of the system Xc−-GSH-GPx4 axis and iron metabolism.

Exogenous biological renal support improves kidney function in rhabdomyolysis-induced acute kidney injury in mice

2021 ◽  
Author(s):  
Chao Liu ◽  
Kun Chi ◽  
Xiaodong Geng ◽  
Quan Hong ◽  
Zhi Mao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Complement System ◽  
Bioinformatics Analysis ◽  
Kidney Injury ◽  
Functional Enrichment ◽  
Muscle Fibres ◽  
Recipient Mouse ◽  
The Complement System ◽  
Renal Support

Abstract BackgroundRhabdomyolysis (RM) is a clinical syndrome characterised by the breakdown of skeletal muscle fibres and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous study, exogenous biological renal support alleviates renal ischaemia-reperfusion injury (IRI) in elderly mice. This study aimed to determine whether exogenous biological renal support promoted renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved.MethodsA parabiosis animal model was established to investigate effects of exogenous biological renal support on RM-induced AKI. Male wild-type C57BL/6 mice and C57BL/6-TgN (ACTb-EGFP) transgenic mice were used to determine whether shared circulation was established among parabiotic pairs 3 weeks after parabiosis surgery. Mice were divided into three groups: the control group (sterile saline injected); RM group (glycerol (8 mL/kg) injected); and parabiosis + RM group (three weeks after the parabiosis model was established, the recipient mouse was injected with glycerol). Blood samples and kidney tissue were collected for further processing 48 hours after RM induction. Bioinformatics analysis was conducted with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, functional enrichment analysis and clustering analysis.ResultsAt 48 hours after the procedure, all mice survived. Exogenous biological renal support attenuated the histological and functional deterioration in RM-induced AKI in mice. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated kidney injury through multiple pathways, including suppressing the complement system; attenuating oxidative stress, inflammation, and apoptosis; and increasing proliferation.ConclusionsExogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and apoptosis; and promoting tubular cell proliferation. Our study provides new ideas for effectively preventing and treating RM-induced AKI and provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.

scholarly journals Exogenous Biological Renal Support Improves Kidney Function in Mice With Rhabdomyolysis-Induced Acute Kidney Injury

2021 ◽  
Vol 8 ◽  
Author(s):  
Chao Liu ◽  
Kun Chi ◽  
Xiaodong Geng ◽  
Quan Hong ◽  
Zhi Mao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Complement System ◽  
Bioinformatics Analysis ◽  
Kidney Injury ◽  
Functional Enrichment ◽  
Control Group ◽  
The Complement System ◽  
Renal Support

Background: Rhabdomyolysis (RM) is a clinical syndrome characterized by breakdown of skeletal muscle fibers and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous research, exogenous biological renal support alleviates renal ischemia–reperfusion injury in elderly mice. This study aimed to determine whether exogenous biological renal support promotes renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved.Methods: A parabiosis animal model was established to investigate the effects of exogenous biological renal support on RM-induced AKI. Mice were divided into three groups: the control group (in which mice were injected with sterile saline), the RM group (in which mice were injected with 8 mL/kg glycerol), and the parabiosis + RM group (in which recipient mice were injected with glycerol 3 weeks after parabiosis model establishment). Blood samples and kidney tissue were collected for further processing 48 h after RM induction. Bioinformatics analysis was conducted via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, functional enrichment analysis, and clustering analysis.Results: No mice died within 48 h after the procedure. Exogenous biological renal support attenuated the histological and functional deterioration in mice with RM-induced AKI. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated AKI through multiple mechanisms, including by suppressing the complement system; attenuating oxidative stress, inflammation, and cell death; and increasing proliferation.Conclusions: Exogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and cell death; and promoting tubular cell proliferation. Our study provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.

scholarly journals Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Junhui Deng ◽  
Wei Tan ◽  
Qinglin Luo ◽  
Lirong Lin ◽  
Luquan Zheng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Rna Binding ◽  
Bioinformatics Analysis ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Cell Models ◽  
Caspase 1 ◽  
Non Coding Rna ◽  
Renal Tubular ◽  
Long Non Coding Rna

Background and Objective: Acute kidney injury (AKI) is a complication of sepsis. Pyroptosis of gasdermin D (GSDMD)-mediated tubular epithelial cells (TECs) play important roles in pathogenesis of sepsis-associated AKI. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), an imprinted gene involved in tumorigenesis, is implicated in pyroptosis occurring in multiple organs. Herein, we investigated the role and mechanisms of MEG3 in regulation of TEC pyroptosis in lipopolysaccharide (LPS)-induced AKI.Materials and Methods: Male C57BL/6 mice and primary human TECs were treated with LPS for 24 h to establish the animal and cell models, respectively, of sepsis-induced AKI. Renal function was assessed by evaluation of serum creatinine and urea levels. Renal tubule injury score was assessed by Periodic acid-Schiff staining. Renal pyroptosis was assessed by evaluating expression of caspase-1, GSDMD, and inflammatory factors IL-1β and IL-18. Cellular pyroptosis was assessed by analyzing the release rate of LDH, expression of IL-1β, IL-18, caspase-1, and GSDMD, and using EtBr and EthD2 staining. MEG3 expression in renal tissues and cells was detected using RT-qPCR. The molecular mechanisms of MEG3 in LPS-induced AKI were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation, dual luciferase reporter gene assays, and a rescue experiment.Results: Pyroptosis was detected in both LPS-induced animal and cell models, and the expression of MEG3 in these models was significantly up-regulated. MEG3-knockdown TECs treated with LPS showed a decreased number of pyroptotic cells, down-regulated secretion of LDH, IL-1β, and IL-18, and decreased expression of GSDMD, compared with those of controls; however, there was no difference in the expression of caspase-1 between MEG3 knockdown cells and controls. Bioinformatics analysis screened out miR-18a-3P, and further experiments demonstrated that MEG3 controls GSDMD expression by acting as a ceRNA for miR-18a-3P to promote TECs pyroptosis.Conclusion: Our study demonstrates that lncRNA MEG3 promoted renal tubular epithelial pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI.

Circular RNA expression profiles in cisplatin-induced acute kidney injury in mice

Epigenomics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1191-1207 ◽  
Author(s):  
Can-Ming Li ◽  
Ming Li ◽  
Zeng-Chun Ye ◽  
Jia-Yan Huang ◽  
Yin Li ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Bioinformatics Analysis ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Cancer Pathways ◽  
Polymerase Chain ◽  
Generation Sequencing

Aim: This study was carried out to identify the expression profile and role of circRNAs in cisplatin-induced acute kidney injury (AKI). Materials & methods: In this study, an AKI model was established in cisplatin-treated mice, and the expression of circRNAs was profiled by next-generation sequencing. The differential expression levels of selected circRNAs were determined by quantitative real-time polymerase chain reaction. Bioinformatics analysis was conducted to predict the functions. Results: In total, 368 circRNAs were detected to be differentially expressed in response to cisplatin treatment. Bioinformatics analysis indicated that the parental genes of the differentially expressed circRNAs were predominantly implicated in the cell and cell part, cellular process and cancer pathways. Conclusion: CircRNAs might be differentially expressed in AKI, which are potentially involved in pathophysiology of cisplatin-induced nephrotoxicity.

scholarly journals Identification of Potential Gene and MicroRNA Biomarkers of Acute Kidney Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Si-Yang Wang ◽  
Jie Gao ◽  
Yu-huan Song ◽  
Guang-Yan Cai ◽  
Xiang-Mei Chen
Keyword(s):  
Acute Kidney Injury ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Protein Protein Interaction ◽  
Treatment Measures ◽  
Subnetwork Analysis

Acute kidney injury (AKI) is a disease that seriously endangers human health. At present, AKI lacks effective treatment methods, so it is particularly important to find effective treatment measures and targets. Bioinformatics analysis has become an important method to identify significant processes of disease occurrence and development. In this study, we analyzed the public expression profile with bioinformatics analysis to identify differentially expressed genes (DEGs) in two types of common AKI models (ischemia-reperfusion injury and cisplatin). DEGs were predicted in four commonly used microRNA databases, and it was found that miR-466 and miR-709 may play important roles in AKI. Then, we found key nodes through protein-protein interaction (PPI) network analysis and subnetwork analysis. Finally, by detecting the expression levels in the renal tissues of the two established AKI models, we found that Myc, Mcm5, E2f1, Oip5, Mdm2, E2f8, miR-466, and miR-709 may be important genes and miRNAs in the process of AKI damage repair. The findings of our study reveal some candidate genes, miRNAs, and pathways potentially involved in the molecular mechanisms of AKI. These data improve the current understanding of AKI and provide new insight for AKI research and treatment.

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