Backround: PLA2R-associated IMN covers 70% of IMN, which is one of the main types of chronic kidney disease in adults and one of the most common causes of end‑stage renal disease. Vascular endothelial growth factor A (VEGFA), a homodimeric vasoactive glycoprotein, is the key mediator of angiogenesis, which lead to numerous kidney diseases, including TSHD7A-associated IMN. However, the role of VEGFA in PLA2R-associated IMN is still poorly understood.Methods: We downloaded the microarray data GSE115857 from GEO. The DEGs were identified with R software, and the functional and pathway enrichment analysis of DEGs was performed utilizing the DAVID and Cytoscape ClueGo plug-in. A comprehensive list of interacting DEGs was constructed using the STRING database and visualized by Cytoscape software. The Cytoscape MCODE and cytoHubba plug-in were used to identify clustered sub-networks, and hub genes from the protein-protein interaction network. Gene set enrichment analysis (GSEA) was used to identify signaling pathway in IMN. Results: There were 1422 genes (952 up-regulated genes and 470 down-regulated genes) were identified as DEGs in GSE115857. The BP of DEGs in GSE115857 was clustered in regulation of transcription from RNA polymerase II promoter, positive regulation of nuclear-transcribed mRNA poly(A) tail shortening, cell adhesion et al. The KEGG pathway of DEGs in GSE115857 was clustered in Rheumatoid arthritis, ABC transporters, PI3K/AKT signaling pathway et al. Then we got a huge PPI network from STRING. 6 modules were screen out to study the functional changes in IMN. The KEGG pathway of module 3 was enriched in soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) interactions in vesicular transport. There were 3 hub genes screened out, namely, VEGFA, JUN,and FOS. Following the random walk, all genes were ranked and GSEA analysis showed that the signaling pathway of DEGs in GSE115857 was focused on angiogenesis, in which VEGFA acts as a core gene. CONCLUSION: In summary, this study reveals VEGFA promotes PLA2R-associated IMN by stimulating angiogenesis via PI3K/AKT signaling. Moreover, SNARE interactions in vesicular transport was involved in the development of PLA2R-associated IMN, which may offer a novel therapeutic strategy in treatment of IMN.
Our research aims to explore the therapeutic effect of circRNA02318 on MIRI rats and the functional mechanism. The MIRI model was constructed in rats. CircRNA02318 overexpressing adenovirus was injected in situ during MIRI perfusion. H9C2 cells were treated with hypoxia for 6 h and reoxygenation for 3 h. Overexpression of circRNA02318 downregulated Drebrin, Nox1, cleaved caspase-3 and Bax in H/R H9C2 cells and MIRI rat heart tissues, promoted the expression of p-Akt/Akt and Bcl-2, and inhibited the apoptosis of H9C2 cells. The volume of myocardial infarction and the release of LDH and TnI in MIRI rats were suppressed by circRNA02318. The Nox1, cleaved caspase-3 and Bax levels were promoted, the level of p-Akt/Akt and Bcl-2 was repressed, and the apoptosis was facilitated by the Drebrin overexpression. Furthermore, the effect of Drebrin overexpression on H9C2 cells was abolished by circRNA02318. Collectively, circRNA02318 exerted therapeutic effects on MIRI rats by inhibiting Drebrin.
Background: It is considered that circRNA can participate in regulating the occurrence and effects of ventricular arrhythmia (VA) through competing endogenous RNA (ceRNA) mechanism, regulating pre-mRNA and regulating parental gene expression. Therefore, we used animal modeling and high-throughput differential screening to screen out circRNA related to VA and study its possible mechanism of action on VA.Methods: The rat model of myocardial ischemia VA was established. High-throughput screening of the differentiated circRNA was conducted and verified by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot. Lv-circRNA01724 lentivirus was constructed using molecular biology.Primary isolation of the rat cardiomyocytes, hypoxia modeling, Lv-circRNA01724 transfection, mode of action verification, and dual luciferase detection of circRNA01724 and miR-323-5p was performed.Results: Through qRT-PCR verification of circRNA01724, circRNA02230, circRNA02088, miR-323-5p, miR-330-5p, and miR-324-3p expressions, circRNA01724 was selected as the research object. Detection by Western blot showed significantly lower Cx43, ZO-1, and α-catenin expressions in rat myocardial tissue in the model group compared with the control group at 1, 7, 14, and 28 days old. On identification of the isolated primary rat cardiomyocytes by immunofluorescence, the α-SMA characteristic protein expression indicated that the isolation was successful. Verification of rat cardiomyocytes transfected with Lv-circRNA01724 suggested overexpression in cells. The miR-323-5p was also highly expressed in the rat cardiomyocyte hypoxia model following Lv-circRNA01724 transfection. Detection by flow cytometry showed that modeling of the transfected Lv-circRNA01724 had a significant increased apoptotic rate.Detection by Western blot showed that modeling of the transfected Lv-circRNA01724 cells had significantly decreased Cx43, ZO-1, and α-catenin compared with the model group.Conclusions: High-throughput screening of circRNA01724 can promote the apoptosis of hypoxic cardiomyocytes, which is related to the rat model of myocardial ischemia VA and may be a potential target for the treatment of VA.
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