bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2020–10–04
seven papers selected by
Nikita Dewani, Max Delbrück Centre for Molecular Medicine
  1. Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission.
  2. An immune-related lncRNA prognostic model in papillary renal cell carcinoma: A lncRNA expression analysis.
  3. Long non-coding RNA HCG18 promotes M1 macrophage polarization through regulating the miR-146a/TRAF6 axis, facilitating the progression of diabetic peripheral neuropathy.
  4. Steroid receptor RNA activator inhibits the migration, invasion and stemness characteristics of renal cell carcinoma cells.
  5. Long non‑coding RNA PLK1S1 was associated with renal cell carcinoma progression by interacting with microRNA‑653 and altering C‑X‑C chemokine receptor 5 expression.
  6. Paclitaxel alleviates the sepsis-induced acute kidney injury via lnc-MALAT1/miR-370-3p/HMGB1 axis.
  7. Long Non-coding RNA IRAIN Inhibits VEGFA Expression via Enhancing Its DNA Methylation Leading to Tumor Suppression in Renal Carcinoma.
  1. Cell Death Dis. 2020 Sep 29. 11(9): 814
    Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission.
    Qiongxia Deng, Ruowei Wen, Sirui Liu, Xiaoqiu Chen, Shicong Song, Xuehong Li, Zhongzhen Su, Cheng Wang.
      Excessive mitochondrial fission plays a key role in podocyte injury in diabetic kidney disease (DKD), and long noncoding RNAs (lncRNAs) are important in the development and progression of DKD. However, lncRNA regulation of mitochondrial fission in podocytes is poorly understood. Here, we studied lncRNA maternally expressed gene 3 (Meg3) in mitochondrial fission in vivo and in vitro using human podocytes and Meg3 podocyte-specific knockdown mice. Expression of lncRNA Meg3 in STZ-induced diabetic mice was higher, and correlated with the number of podocytes. Excessive mitochondrial fission of podocytes and renal histopathological and physiological parameters were improved in podocyte-specific Meg3 knockdown diabetic mice. Elongated mitochondria with attenuated podocyte damage, as well as mitochondrial translocation of dynamin-related protein 1 (Drp1), were decreased in Meg3 knockout podocytes. By contrast, increased fragmented mitochondria, podocyte injury, and Drp1 expression and phosphorylation were observed in lncRNA Meg3-overexpressing podocytes. Treatment with Mdivi1 significantly blunted more fragmented mitochondria and reduced podocyte injury in lncRNA Meg3-overexpressing podocytes. Finally, fragmented mitochondria and Drp1 mitochondrial translocation induced by high glucose were reduced following treatment with Mdivi1. Our data show that expression of Meg3 in podocytes in both human cells and diabetic mice was higher, which regulates mitochondrial fission and contributes to podocyte injury through increased Drp1 and its translocation to mitochondria.
    DOI:  https://doi.org/10.1038/s41419-020-03022-7
  2. Genomics. 2020 Sep 23. pii: S0888-7543(20)31184-8. [Epub ahead of print]
    An immune-related lncRNA prognostic model in papillary renal cell carcinoma: A lncRNA expression analysis.
    Shao-Hao Chen, Fei Lin, Jun-Ming Zhu, Zhi-Bin Ke, Ting-Ting Lin, Yun-Zhi Lin, Xue-Yi Xue, Yong Wei, Qing-Shui Zheng, Ye-Hui Chen, Ning Xu.
       OBJECTIVE: To screen several immune-related long non-coding RNAs (lncRNAs) and construct a prognostic model for papillary renal cell carcinoma (pRCC).
    METHODS: Transcriptome-sequencing data of pRCC was downloaded and a prognostic model was constructed. Time-dependent receiver operating characteristic (ROC) curve was plotted and the area under curve (AUC) was calculated. We conducted quantitative reverse transcription polymerase chain reaction (RT-PCR) to verify the model. The gene set enrichment analysis (GSEA) was used to show the connection of our model with immune pathways.
    RESULT: We identified four lncRNAs to constructed the model. The model was significantly associated with the survival time and survival state. The expression-levels of the four lncRNAs were measured and the prognosis of high-risk patients was significantly worse. The two immune-gene sets had an active performance in the high-risk patients.
    CONCLUSION: We constructed a prognostic model in pRCC which provided more reference for treatment.
    Keywords:  Bioinformatics; Immune; Long non-coding RNA; Papillary renal cell carcinoma; Prognosis
    DOI:  https://doi.org/10.1016/j.ygeno.2020.09.046
  3. Mol Cell Biochem. 2020 Sep 29.
    Long non-coding RNA HCG18 promotes M1 macrophage polarization through regulating the miR-146a/TRAF6 axis, facilitating the progression of diabetic peripheral neuropathy.
    Wei Ren, Guangxia Xi, Xing Li, Lingxia Zhao, Kun Yang, Xuemei Fan, Linlin Gao, Hongmei Xu, Jianjin Guo.
      Diabetic peripheral neuropathy (DPN) is one of the most important complications in diabetes mellitus (DM), which has been reported to be modulated by long non-coding RNAs (lncRNAs). The purpose of the current study is to explore the regulatory mechanism of lncRNA HCG18 on DPN in vitro. The expression of lncRNA HCG18, miR-146a, TRAF6, CD11c, and iNOS was detected by qRT-PCR. Through Enzyme-linked immunosorbent assay, the levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were determined. M1 macrophage polarization was measured by flow cytometry analysis. The interactions between miR-146a and HCG18/TRAF6 were predicted by Starbase/Targetscan software and verified by the dual luciferase reporter assay. Western blot assay was performed to determine the protein expression of TRAF6. LncRNA HCG18 was highly expressed in DPN model and HG-induced macrophages. The levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were elevated in DPN model. The expression of M1 markers (CD11c and iNOS) was visibly up-regulated in DPN model and was positively correlated with HCG18 expression. LncRNA HCG18 facilitated M1 macrophage polarization. In addition, miR-146a was identified as a target of lncRNA HCG18. Overexpression of miR-146a reversed the promoting effect of HCG18 on M1 macrophage polarization. Simultaneously, TRAF6 was a target gene of miR-146a TRAF6 expression was positively modulated by HCG18 and was negatively modulated by miR-146a. Down-regulation of TRAF6 reversed the promoting effect of HCG18 on M1 macrophage polarization. LncRNA HCG18 promotes M1 macrophage polarization via regulating the miR-146a/TRAF6 axis, facilitating the progression of DPN. This study provides a possible therapeutic strategy for DPN.
    Keywords:  Diabetic peripheral neuropathy; Macrophage polarization; TRAF6; lncRNA HCG18; miR-146a
    DOI:  https://doi.org/10.1007/s11010-020-03923-3
  4. Int J Mol Med. 2020 Nov;46(5): 1765-1776
    Steroid receptor RNA activator inhibits the migration, invasion and stemness characteristics of renal cell carcinoma cells.
    Chanjuan Zhang, Neng Zhu, Chan Liu, Hongtao Wu, Yantao Yin, Yaning Shi, Duanfang Liao, Li Qin.
      Renal cell carcinoma (RCC) has a high mortality rate among urological malignancies, and its underlying mechanisms remain unclear. Steroid receptor RNA coactivator (SRA) belongs to the long non‑coding RNAs (lncRNAs) and has been demonstrated to be closely related to various types of cancer. In the present study, the decreased expression level of SRA was first confirmed in RCC tissues and cell lines by RT‑qPCR. Using knockdown or overexpression systems, it was then found that SRA inhibited the proliferation of RCC cell lines and promoted their apoptosis. In addition, SRA suppressed the migration and invasion, and altered EMT‑related markers in RCC cells. More importantly, it was demonstrated that SRA reduced percentage of CD44+/CD24‑ cells and the sphere‑forming efficiency. SRA also attenuated the expression levels of CD44, SOX‑2, ABCG2 and OCT‑4, which are all associated with cancer cell stemness characteristics. Although SRA increased the phosphorylation of extracellular‑regulated protein kinase (ERK), the ERK1/2 pathway could not further interfere with the alteration of EMT‑related markers mediated by SRA. Notably, the ERK inhibitor, PD98059, abolished ERK1/2 phosphorylation, whereas it did not exert any marked effects on cell proliferation and EMT‑related markers mediated by SRA. Taken together, the findings of the present study indicate that SRA is an important molecule that inhibits the migration, invasion and stem cell characteristics of RCC cells; the ERK signaling pathway may not be involved in this process.
    DOI:  https://doi.org/10.3892/ijmm.2020.4730
  5. Oncol Rep. 2020 Nov;44(5): 1985-1996
    Long non‑coding RNA PLK1S1 was associated with renal cell carcinoma progression by interacting with microRNA‑653 and altering C‑X‑C chemokine receptor 5 expression.
    Weiyuan Li, Dengke Yang, Yu Zhang, Shutian Zhao, Dong Li, Min Liu.
      Renal cell carcinoma (RCC) is the most common type of renal cancer. Long non‑coding RNA (lncRNA) has been reported to play a vital role in the development and progression of various types of cancer type. However, the underlying molecular mechanisms of PLK1S1 in regulating RCC progression remain unclear. In the present study, PLK1S1 was upregulated in RCC tissues and cells, and PLK1S1 expression was also significantly elevated in stage IV RCC tissues. Kaplan‑Meier analysis showed that patients with high PLK1S1 expression had a shorter overall survival time compared with those with low PLK1S1 expression. Moreover, bioinformatics analysis and luciferase reporter assay demonstrated that PLK1S1 inhibited microRNA (miR)‑653 expression by direct interaction. Functional analyses demonstrated that a miR‑653 inhibitor promoted short hairpin PLK1S1‑attenuated cell proliferation, invasion and sorafenib resistance of RCC cells. In addition, C‑X‑C motif chemokine receptors 5 (CXCR5) was identified as an effector of PLK1S1/miR‑653‑mediated tumorigenesis and drug resistance in RCC cells. Lastly, xenograft experiments demonstrated that PLK1S1 knockdown inhibited tumor growth in vivo. Reverse transcription‑quantitative PCR and western blot analysis revealed that PLK1S1 knockdown upregulated the expression level of miR‑653, whilst downregulating the expression level of CXCR5. In conclusion, the present study revealed that PLK1S1 promoted tumor progression and sorafenib resistance in RCC through regulation of the miR‑653/CXCR5 axis, which may offer a novel treatment strategy for patients with RCC.
    DOI:  https://doi.org/10.3892/or.2020.7742
  6. Life Sci. 2020 Sep 27. pii: S0024-3205(20)31258-3. [Epub ahead of print] 118505
    Paclitaxel alleviates the sepsis-induced acute kidney injury via lnc-MALAT1/miR-370-3p/HMGB1 axis.
    Lina Xu, Guyong Hu, Pengcheng Xing, Minjie Zhou, Donglian Wang.
       AIMS: To investigate the effects of paclitaxel on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and its related mechanisms.
    MAIN METHODS: The sepsis-associated AKI was induced by LPS using HK-2 cells. Then the mRNA and protein expression levels of relevant genes in the serum of sepsis patients and HK-2 cells with LPS-induced AKI were detected by qRT-PCR and western blot analyses before and after paclitaxel treatment, respectively. Subsequently, the cell counting kit-8 (CCK-8) and flow cytometry assays were performed to estimate the effects of paclitaxel, lnc-MALAT1, miR-370-3p and HMGB1 on the proliferation and apoptosis of HK-2 cells injured by LPS.
    KEY FINDINGS: Lnc-MALAT1 was increased both in the serum of sepsis patients and cells injured by LPS, which could inhibit the cell proliferation, promote the cell apoptosis and increase the expression of TNF-α, IL-6 and IL-1β caused by paclitaxel. Moreover, lnc-MALAT1 was sponged with miR-370-3p which had the inverse effects with lnc-MALAT1 in LPS induced HK-2 cells. What's more, miR-370-3p targeted HMGB1 which was induced in serum and cells of sepsis. Knockdown of miR-370-3p inhibited the expression of HMGB1 and suppressed the proliferation but promoted the apoptosis of HK-2 cells injured by LPS as well as the expression of TNF-α, IL-6 and IL-1β. Besides, paclitaxel restrained the expression of HMGB1 via regulating lnc-MALAT1/miR-370-3p axis.
    SIGNIFICANCE: Paclitaxel could protect against LPS-induced AKI via the regulation of lnc-MALAT1/miR-370-3p/HMGB1 axis and the expression of TNF-α, IL-6 and IL-1β, revealing that paclitaxel might act as a therapy drug in reducing sepsis-associated AKI.
    Keywords:  Acute kidney injury; Chinese traditional medicine; HMGB1; Sepsis; lnc-MALAT1; miR-370-3p
    DOI:  https://doi.org/10.1016/j.lfs.2020.118505
  7. Front Oncol. 2020 ;10 1082
    Long Non-coding RNA IRAIN Inhibits VEGFA Expression via Enhancing Its DNA Methylation Leading to Tumor Suppression in Renal Carcinoma.
    Yang Li, Qingyang Luo, Zun Li, Yun Wang, Chaoyang Zhu, Tieqiang Li, Xiaodong Li.
      Aims: Long non-coding RNA IRAIN (lncRNA IRAIN) plays a critical role in numerous malignancies. However, the function of lncRNA IRAIN in renal carcinoma (RC) remains enigmatic. The purpose of this study is to characterize the effects of lncRNA IRAIN on RC progression. Methods: The expression pattern of lncRNA IRAIN and the vascular endothelial growth factor A (VEGFA) in RC tissues and cells was characterized by RT-qPCR and Western blot analysis. The roles of lncRNA IRAIN and VEGFA in the progression of RC were studied by gain- or loss-of-function experiments. Bioinformatics data analysis was used to predict CpG islands in the VEGFA promoter region. MSP was applied to detect the level of DNA methylation in RC cells. The interaction between lncRNA IRAIN and VEGFA was identified by RNA immunoprecipitation and RNA-protein pull down assays. Recruitment of DNA methyltransferases (Dnmt) to the VEGFA promoter region was achieved by chromatin immunoprecipitation. The subcellular localization of lncRNA IRAIN was detected by fractionation of nuclear and cytoplasmic RNA. Cell viability was investigated by CCK-8 assay, cell migration was tested by transwell migration assay, and apoptosis was analyzed by flow cytometry. The expression of epithelial-mesenchymal transition-related and apoptotic factors was evaluated by Western blot analysis. Finally, the effect of the lncRNA IRAIN/VEGFA axis was confirmed in an in vivo tumor xenograft model. Results: LncRNA IRAIN was poorly expressed in RC tissues and cells with a primary localization in the nucleus, while VEGFA was highly expressed. Overexpression of lncRNA IRAIN or knockdown of VEGFA inhibited cell proliferation and migration and induced the apoptosis of RC cells. Bioinformatics analysis indicated the presence of CpG islands in the VEGFA promoter region. Lack of methylation at specific sites in the VEGFA promoter region was detected through MSP assay. We found that lncRNA IRAIN was able to inhibit VEGFA expression through recruitment of Dnmt1, Dnmt3a, and Dnmt3b to the VEGFA promoter region. LncRNA IRAIN was also able to suppress RC tumor growth via repression of VEGFA in an in vivo mouse xenograft model. Conclusion: Our data shows that by downregulating VEGFA expression in RC, the lncRNA IRAIN has tumor-suppressive potential.
    Keywords:  DNA methylation; DNA methyltransferase; long non-coding RNA IRAIN; renal carcinoma; tumor development; tumor progression; tumor-suppressive potential; vascular endothelial growth factor A
    DOI:  https://doi.org/10.3389/fonc.2020.01082
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