Upregulation of microRNA‐424 relieved diabetic nephropathy by targeting Rictor through mTOR Complex2/Protein Kinase B signaling

Wang, Guofeng; Yan, Yue; Xu, Ning; Yuan, Hui; Yin, Dong

doi:10.1002/jcp.27822

Cited by 35 publications

(27 citation statements)

References 23 publications

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“…Increasing evidences have demonstrated that miRNAs play a key role in the pathogenesis of DN [29,30]. For example, Wang et al [31] found that miR-424 was down-regulated in renal tissues of DN rats and up-regulation of miR-424 obviously improved the symptoms in DN rat models by targeting Rictor. Yu et al [32] showed that miR-370 was overexpressed in a rat model of DN and up-regulation of miR-370 promoted mesangial cell proliferation and extracellular matrix (ECM) by suppressing CNPY1 in DN rat models.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-140-5p ameliorates the high glucose-induced apoptosis and inflammation through suppressing TLR4/NF-κB signaling pathway in human renal tubular epithelial cells

Ren

Chen

et al. 2020

Bioscience Reports

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Hyperglycemia-induced renal tubular cell injury is thought to play a critical role in the pathogenesis of diabetic nephropathy (DN). However, the role of miRNAs in renal tubular cell injury remains to be fully elucidated. The aim of the present study was to investigate the role and mechanisms of miRNAs protecting against high glucose (HG)-induced apoptosis and inflammation in renal tubular cells. First, we analyzed microRNA (miRNA) expression profiles in kidney tissues from DN patients using miRNA microarray. It was observed that miRNA-140-5p (miR-140-5p) was significantly down-regulated in kidney tissues from patients with DN. An inverse correlation between miR-140-5p expression levels with serum proteinuria was observed in DN patients, suggesting miR-140-5p may be involved in the progression of DN. HG-induced injury in HK-2 cells was used to explore the potential role of miR-140-5p in DN. We found that miR-140-5p overexpression improved HG-induced cell injury, as evidenced by the enhancement of cell viability, and inhibition of the activity of caspase-3 and reactive oxygen species (ROS) generation. It was also observed that up-regulation of miR-140-5p suppressed HG induced the expressions of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in HK-2 cells. In addition, TLR4, one of the upstream molecules of NF-κB signaling pathway, was found to be a direct target of miR-140-5p in the HK-2. Moreover, the HG-induced activation of NF-κB signaling pathway was inhibited by miR-140-5p overexpression. These results indicated that miR-140-5p protected HK-2 cells against HG-induced injury through blocking the TLR4/NF-κB pathway, and miR-140-5p may be considered as a potential prognostic biomarker and therapeutic target in the treatment of DN.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-140-5p ameliorates the high glucose-induced apoptosis and inflammation through suppressing TLR4/NF-κB signaling pathway in human renal tubular epithelial cells

Ren

Chen

et al. 2020

Bioscience Reports

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“…Increasing evidence has revealed that miRNAs serve critical roles in the pathogenesis of DN. For example, Wang et al ( 26 ) reported that miR-424 overexpression prevented the occurrence and progression of DN by targeting RPTOR independent companion of MTOR complex 2 in rats. Moreover, Yang et al ( 27 ) observed that miR-214 suppressed oxidative stress in DN via the reactive oxygen species/Akt/mTOR signaling pathway in proximal tubular cells.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑199a‑3p suppresses high glucose‑induced apoptosis and inflammation by regulating the IKKβ/NF‑κB signaling pathway in renal tubular epithelial cells

2020

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Renal tubular epithelial cells (RTEC) injury induced by hyperglycemia is considered a major contributor to the pathogenesis of diabetic nephropathy (DN). However, few studies have focused on the role of microRNAs (miRNAs/miRs) in RTEC injury. Therefore, the present study aimed to investigate the role and mechanisms of miRNAs in RTEC injury. In the study, miRNAs expression profiles were determined via microarray assay in the peripheral blood samples of patients with DN. High glucose (HG)-induced injury in HK-2 cells was used as a cell model to examine the potential role of miR-199a-3p in DN. The expression of miR-199a-3p was validated using reverse transcription-quantitative PCR. The expressions of TNF-α, IL-1β and IL-6, were detected via ELISA. The protein levels of apoptosis-related proteins were determined using western blotting. Cell apoptosis and caspase 3 activity were evaluated via flow cytometry analysis and caspase 3 activity assay, respectively. Luciferase reporter assay was used to confirm the interaction between miR-199a-3p and IKKβ. miR-199a-3p was found to be significantly downregulated in the peripheral blood samples, and there was a negative correlation between miR-199a-3p expression and proteinuria in patients with DN. It was identified that miR-199a-3p expression was time-dependently decreased in the HG-induced cell damage model. Moreover, miR-199a-3p overexpression significantly improved HG-induced cell injury, as evidenced by the decrease in cell apoptosis and inflammation. Subsequent analyses demonstrated that miR-199a-3p directly targeted IKKβ, whose expression was increased, and negatively correlated with miR-199a-3p expression in patients with DN. The protective effects of miR-199a-3p overexpression on HG-treated HK-2 cells were partially reversed by IKKβ overexpression. In addition, activation of the NF-κB pathway by HG was blocked by miR-199a-3p mimics transfection in HK-2 cells. Collectively, the present findings indicated that miR-199a-3p protected HK-2 cells against HG-induced injury via inactivation of the IKKβ/NF-κB pathway, suggesting enhanced expression of miR-199a-3p as a potential therapeutic strategy for patients with DN.

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“…As shown in the GO enrichment analysis results, the potential targets of shenzhuo formula acting on DN were mainly associated with various biological processes, such as lipopolysaccharide-mediated signaling pathway, inflammatory response, positive regulation of cyclase activity, protein kinase B signaling, positive regulation of MAP kinase activity, response to estradiol, which have a strongly direct correlation with the pathogenesis of DN [28][29][30][31][32][33][34].…”

Section: Discussionmentioning

confidence: 94%

Network Pharmacology-based Prediction of Mechanism of Shenzhuo Formula for Application to DN

Wang

Han

Zhang

et al. 2020

Preprint

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Background: Shenzhuo formula is a traditional Chinese medicine (TCM) prescription which has significant therapeutic effects on diabetic nephropathy (DN). However, its mechanism remains unknown. Therefore, this study aimed to explore the underlying anti-DN mechanism of shenzhuo formula.Methods: The active ingredients and targets of shenzhuo formula were obtained by searching TCMSP, TCMID, SwissTargetPrediction and HIT. The DN target was identified from TTD, DrugBank and DisGeNet. The potential targets were obtained and PPI network were built after mapping the disease and drug targets. The key targets were screened out by network topology and the “drugs - DN - key targets” network was constructed by Cytoscape. GO analysis and KEGG pathway enrichment analysis were performed using DAVID, and the results were visualized using the Omicshare Tools.Results: We obtained 182 potential targets and 30 key targets. Ulteriorly, “drugs - DN - key targets” network were constructed, and results showed that nodes like M51, M21, M5, M71, M28, EGFR, MMP9, MAPK8, PIK3CA and STAT3 had a higher degree. GO analysis results mainly involved in positive regulation of transcription from RNA polymerase II promoter, inflammatory response, lipopolysaccharide-mediated signalingpathway and other biological processes. The results of KEGG showed that DN-related pathways like TNF signaling pathway, PI3K-Akt signaling pathway were at the top of the list.Conclusion: This article reveals the possible mechanism of shenzhuo formula in the treatment of DN through network pharmacology research, and lays a foundation for further studies.

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Upregulation of microRNA‐424 relieved diabetic nephropathy by targeting Rictor through mTOR Complex2/Protein Kinase B signaling

Cited by 35 publications

References 23 publications

MicroRNA-140-5p ameliorates the high glucose-induced apoptosis and inflammation through suppressing TLR4/NF-κB signaling pathway in human renal tubular epithelial cells

MicroRNA-140-5p ameliorates the high glucose-induced apoptosis and inflammation through suppressing TLR4/NF-κB signaling pathway in human renal tubular epithelial cells

MicroRNA‑199a‑3p suppresses high glucose‑induced apoptosis and inflammation by regulating the IKKβ/NF‑κB signaling pathway in renal tubular epithelial cells

Network Pharmacology-based Prediction of Mechanism of Shenzhuo Formula for Application to DN

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