bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2021–07–04
six papers selected by
Nikita Dewani, Max Delbrück Centre for Molecular Medicine
  1. Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease.
  2. Knockdown of lncRNA NORAD inhibits the proliferation, inflammation and fibrosis of human mesangial cells under high-glucose conditions by regulating the miR-485/NRF1 axis.
  3. Non-Coding RNAs in Kidney Diseases: The Long and Short of Them.
  4. A prognostic nomogram based on competing endogenous RNA network for clear-cell renal cell carcinoma.
  5. LncRNA HCP5 knockdown inhibits high glucose-induced excessive proliferation, fibrosis and inflammation of human glomerular mesangial cells by regulating the miR-93-5p/HMGA2 axis.
  6. Targeted Demethylation of the PLOD2 mRNA Inhibits the Proliferation and Migration of Renal Cell Carcinoma.
  1. Int J Mol Sci. 2021 Jun 02. pii: 6027. [Epub ahead of print]22(11):
    Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease.
    Swayam Prakash Srivastava, Julie E Goodwin, Pratima Tripathi, Keizo Kanasaki, Daisuke Koya.
      Large-scale RNA sequencing and genome-wide profiling data revealed the identification of a heterogeneous group of noncoding RNAs, known as long noncoding RNAs (lncRNAs). These lncRNAs play central roles in health and disease processes in diabetes and cancer. The critical association between aberrant expression of lncRNAs in diabetes and diabetic kidney disease have been reported. LncRNAs regulate diverse targets and can function as sponges for regulatory microRNAs, which influence disease phenotype in the kidneys. Importantly, lncRNAs and microRNAs may regulate bidirectional or crosstalk mechanisms, which need to be further investigated. These studies offer the novel possibility that lncRNAs may be used as potential therapeutic targets for diabetes and diabetic kidney diseases. Here, we discuss the functions and mechanisms of actions of lncRNAs, and their crosstalk interactions with microRNAs, which provide insight and promise as therapeutic targets, emphasizing their role in the pathogenesis of diabetes and diabetic kidney disease.
    Keywords:  EMT; EndMT; diabetes mellitus; diabetic kidney disease; kidney fibrosis; long noncoding RNAs; microRNAs in kidney
    DOI:  https://doi.org/10.3390/ijms22116027
  2. Exp Ther Med. 2021 Aug;22(2): 874
    Knockdown of lncRNA NORAD inhibits the proliferation, inflammation and fibrosis of human mesangial cells under high-glucose conditions by regulating the miR-485/NRF1 axis.
    Linna Wang, Xiaoying Yuan, Lifeng Lian, Huali Guo, Hongxia Zhang, Minghui Zhang.
      Long non-coding RNAs (lncRNAs) serve major roles in diabetic nephropathy (DN). The present study investigated the regulatory mechanism of lncRNA non-coding RNA activated by DNA damage (NORAD) on DN in vitro. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of lncRNA NORAD, microRNA-485 (miR-485) and nuclear respiratory factor 1 (NRF1) in the tissues of patients with DN and high-glucose (HG)-induced human mesangial cells (HMCs). The viability of HMCs was determined using an MTT assay. The levels of inflammatory [tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6] and fibrotic [type IV collagen (Col. IV), fibronectin (FN) and plasminogen activator inhibitor 1 (PAI-1)] factors in HMCs were measured by ELISA. The interactions between miR-485 and NORAD/NRF1 were predicted using StarBase and miRDB softwares and confirmed by a dual-luciferase reporter assay. Western blot analysis was utilized to measure NRF1 protein levels. lncRNA NORAD was highly expressed in tissues and HG-induced HMCs. NORAD knockdown suppressed cell viability in HG-induced HMCs. The levels of the inflammatory and fibrotic factors in HG-induced HMCs were inhibited by NORAD knockdown. miR-485 was the direct target of NORAD. NORAD reversed the inhibitory effects of miR-485 on HG-induced HMCs. Furthermore, NRF1 was the target gene of miR-485. Downregulation of miR-485 and upregulation of NRF1 reversed the inhibitory effects of NORAD knockdown on HG-induced HMCs. NORAD knockdown inhibited HG-induced HMC proliferation, inflammation and fibrosis by regulating miR-485/NRF1, providing a possible therapeutic strategy for DN.
    Keywords:  diabetic nephropathy; high-glucose; microRNA-485; non-coding RNA activated by DNA damage; nuclear respiratory factor 1
    DOI:  https://doi.org/10.3892/etm.2021.10306
  3. Int J Mol Sci. 2021 Jun 04. pii: 6077. [Epub ahead of print]22(11):
    Non-Coding RNAs in Kidney Diseases: The Long and Short of Them.
    Juan Antonio Moreno, Eya Hamza, Melania Guerrero-Hue, Sandra Rayego-Mateos, Cristina García-Caballero, Mercedes Vallejo-Mudarra, Laurent Metzinger, Valérie Metzinger-Le Meuth.
      Recent progress in genomic research has highlighted the genome to be much more transcribed than expected. The formerly so-called junk DNA encodes a miscellaneous group of largely unknown RNA transcripts, which contain the long non-coding RNAs (lncRNAs) family. lncRNAs are instrumental in gene regulation. Moreover, understanding their biological roles in the physiopathology of many diseases, including renal, is a new challenge. lncRNAs regulate the effects of microRNAs (miRNA) on mRNA expression. Understanding the complex crosstalk between lncRNA-miRNA-mRNA is one of the main challenges of modern molecular biology. This review aims to summarize the role of lncRNA on kidney diseases, the molecular mechanisms involved, and their function as emerging prognostic biomarkers for both acute and chronic kidney diseases. Finally, we will also outline new therapeutic opportunities to diminish renal injury by targeting lncRNA with antisense oligonucleotides.
    Keywords:  IgA nephropathy; acute kidney disease; chronic kidney disease; gene regulation; long non-coding RNA; microRNA; non-coding RNA
    DOI:  https://doi.org/10.3390/ijms22116077
  4. Cancer Med. 2021 Jun 30.
    A prognostic nomogram based on competing endogenous RNA network for clear-cell renal cell carcinoma.
    Yun Peng, Shangrong Wu, Zihan Xu, Dingkun Hou, Nan Li, Zheyu Zhang, Lili Wang, Haitao Wang.
       BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is stubborn to traditional chemotherapy and radiation treatment, which makes its clinical management a major challenge. Recently, we have made efforts in understanding the etiology of ccRCC. Increasing evidence revealed that the competing endogenous RNA (ceRNA) was involved in the development of varied tumors. However, a comprehensive analysis of the prognostic model based on lncRNA-miRNA-mRNA ceRNA regulatory network of ccRCC with large-scale sample size and RNA-sequencing expression data is still limited.
    METHODS: RNA-sequencing expression data were taken out from GTEx database and TCGA database, a total of 354 samples with ccRCC and 157 normal controlled samples were included in our study. The ccRCC-specific genes were obtained by WGCNA and differential expression analysis. Following, the communication of mRNAs and lncRNAs with targeted miRNAs were predicted by MiRcode, starBase, miRTarBase, and TargetScan. A gene signature of eight genes was further constructed by univariate Cox regression, Lasso methods, and multivariate Cox regression analysis.
    RESULTS: A total of 2191 mRNAs and 1377 lncRNAs was identified, and a dysregulated ceRNA network for ccRCC was established using 7 mRNAs, 363 lncRNAs, and 3 miRNAs. Further, a gene signature including eight genes based on this ceRNA was determined followed by the development of a nomogram predicting 1-, 3-, and 5-year survival probability for ccRCC.
    CONCLUSION: It could contribute to a better understanding of ccRCC tumorigenesis mechanism and guide clinicians to make a more accurate treatment decision.
    Keywords:  competing endogenous RNA; gene signature; nomograms; renal cell carcinoma
    DOI:  https://doi.org/10.1002/cam4.4109
  5. BMC Endocr Disord. 2021 Jun 29. 21(1): 134
    LncRNA HCP5 knockdown inhibits high glucose-induced excessive proliferation, fibrosis and inflammation of human glomerular mesangial cells by regulating the miR-93-5p/HMGA2 axis.
    Xuan Wang, Yan Liu, Jian Rong, Kai Wang.
       BACKGROUND: Long non-coding RNAs (lncRNAs) are widely reported to be involved in the development of human diseases. HLA complex P5 (HCP5) deregulation is associated with various diseases. However, the function of HCP5 in diabetic nephropathy (DN) is unclear.
    METHODS: Human glomerular mesangial cells (HGMCs) were treated with high glucose (HG) to establish DN cell models. The expression of HCP5, miR-93-5p and high mobility group AT-hook 2 (HMGA2) mRNA was detected using quantitative polymerase chain reaction (QPCR). Cell proliferation and cell apoptosis were assessed using cell counting kit-8 (CCK-8) assay and flow cytometry assay, respectively. The expression of apoptosis- and fibrosis-related proteins and HMGA2 protein was quantified by western blot. The release of pro-inflammatory factor was checked using enzyme-linked immunosorbent assay (ELISA). The predicted relationship between miR-93-5p and HCP5 or HMGA2 was verified using dual-luciferase reporter assay, pull-down assay or RNA immunoprecipitation (RIP) assay.
    RESULTS: The expression of HCP5 and HMGA2 was enhanced, while the expression of miR-93-5p was declined in DN serum samples and HG-treated HGMCs. HCP5 knockdown or miR-93-5p restoration ameliorated HG-induced HGMC proliferation, fibrosis and inflammation. MiR-93-5p was a target of HCP5, and miR-93-5p inhibition reversed the effects caused by HCP5 knockdown. Moreover, HMGA2 was a target of miR-93-5p, and HMGA2 overexpression abolished the effects of miR-93-5p restoration. HCP5 knockdown inhibited the AKT/mTOR signaling pathway.
    CONCLUSION: HCP5 was implicated in DN progression by modulating the miR-93-5p/HMGA2 axis, which provided new insights into the understanding of DN pathogenesis.
    Keywords:  Diabetic nephropathy; HCP5; HMGA2; High glucose; miR-93-5p
    DOI:  https://doi.org/10.1186/s12902-021-00781-y
  6. Front Mol Biosci. 2021 ;8 675683
    Targeted Demethylation of the PLOD2 mRNA Inhibits the Proliferation and Migration of Renal Cell Carcinoma.
    Congcong Cao, Qian Ma, Xinbo Huang, Aolin Li, Jun Liu, Jing Ye, Yaoting Gui.
      N6-methyladenosine (m6A) RNA modification is the most common internal mRNA modification in mammals and has been reported to play a key role in gene expression regulation. In this study, we detected a high level of m6A methylation of the PLOD2 3'-untranslated regions (3'UTR) in renal cell carcinoma (RCC). Furthermore, we found that the high expression level of PLOD2 was a prognostic indicator for patients with RCC. A dm6ACRISPR demethylation system was performed to accurately and specifically demethylate 3'UTR of PLOD2 and caused an inactivation of PLOD2 expression. Furthermore, we also performed many in vitro experiments to confirm that PLOD2 exerted tumor promoter effects by promoting tumor proliferation and migration. In conclusion, PLOD2 mRNA demethylated by dCas13b-ALKBH5 might provide a new light on the treatment for RCC.
    Keywords:  (N6-methyladenosine); CRISPR; PLOD2; dCas13b; renal cell cancer
    DOI:  https://doi.org/10.3389/fmolb.2021.675683
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