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Long Non-coding RNA H19 Augments Hypoxia/Reoxygenation-Induced Renal Tubular Epithelial Cell Apoptosis and Injury by the miR-130a/BCL2L11 Pathway.

ABSTRACT: Acute kidney injury (AKI) is a severe kidney disease defined by partial or abrupt loss of renal function. Emerging evidence indicates that non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs), function as essential regulators in AKI development. Here we aimed to explore the underlying molecular mechanism of the lncRNA H19/miR-130a axis for the regulation of inflammation, proliferation, and apoptosis in kidney epithelial cells. Human renal proximal tubular cells (HK-2) were induced by hypoxia/reoxygenation to replicate the AKI model in vitro. After treatment, the effects of LncRNA H19 and miR-130a on proliferation and apoptosis of HK-2 cells were investigated by CCK-8 and flow cytometry. Meanwhile, the expressions of LncRNA H19, miR-130a, and inflammatory cytokines were detected by qRT-PCR, western blot, and ELISA assays. The results showed that downregulation of LncRNA H19 could promote cell proliferation, inhibit cell apoptosis, and suppress multiple inflammatory cytokine expressions in HK-2 cells by modulating the miR-130a/BCL2L11 pathway. Taken together, our findings indicated that LncRNA H19 and miR-130a might represent novel therapeutic targets and early diagnostic biomarkers for the treatment of AKI.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC7952615 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcute kidney injury (AKI) is a common clinically critical illness with serious consequences for the patients. Shenshuaikang enema (SE) is a Chinese herbal compound that is used to treat AKI in clinical practice. However, its mechanism of action remains unclear.AimThe aim of this study was to investigate the therapeutic effect of SE and explore the molecular mechanisms using network pharmacology and in vitro experiments.Materials and methodsThe herb-component-target network was constructed based on network pharmacology. The predicted targets and pathways were validated using in vitro experiments. A renal tubular epithelial cell line (HK-2 cells) was exposed to hypoxia and reoxygenation (H/R) using air-tight conditions for five hours and treated with different concentrations of SE (25%, 50%, and 75%) to assess cell viability and apoptosis and determine the optimal experimental dose. Subsequently, H/R-injured HK-2 cells were pretreated with the optimal SE dose and then randomly divided into three groups, the SE, SE-SP600125 (inhibitor of JNK), and SE-NAC (antioxidant) groups. The cell vitality, apoptosis, and death were evaluated using the cell counting kit 8 (CCK8) and carboxyfluorescein succinimidyl ester/propidium iodide (CFSF/PI) staining. The apoptosis-related protein JNK and Caspase-3 were assessed by Western blot. Expression of JNK and Caspase-3 genes was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR).Results123 active components and 226 targets were identified from four herbs that composed the herb-compound-target network based on transcriptomics and network pharmacology analyses. The KEGG pathway analyses revealed that the mitochondrial apoptosis pathway was involved in the therapeutic AKI effects of SE. Cell vitality of H/R-induced HK-2 cells was obviously increased when treating them with SE, and the apoptosis was significantly inhibited, especially in the SE (50%) group at 4 and 12 h after modeling. Pretreatment with antioxidant NAC obviously prevented cell death compared to the SE (50%) group, while no obvious reduction of apoptosis was observed in the SP600125 group. JNK expression level was significantly increased in the SE (50%) group compared to the SP600125 (P < 0.01) and the NAC group (P < 0.05). Caspase-3 was downregulated in the SE (50%) group compared to the SP600125 (P < 0.01) and NAC group (P < 0.05). Caspase-3 activation in the SP600125 group was higher than that in the NAC group (P < 0.05). Moreover, the oxidative damage-dependent JNK/Caspase-3 pathway was identified in the H/R-injured HK-2 cells by inhibiting the JNK activation and oxidative damage.ConclusionsOur findings suggested that the H/R-triggered apoptosis in HK-2 cells was abrogated by SE by upregulating the oxidative damage-dependent JNK to trigger suppression of Caspase-3.

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Long Non-coding RNA H19 Augments Hypoxia/Reoxygenation-Induced Renal Tubular Epithelial Cell Apoptosis and Injury by the miR-130a/BCL2L11 Pathway.

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