bims-lorfki 2021-04-25 papers

bims-lorfki

Biomed News

on Long non-coding RNA functions in the kidney

Issue of 2021–04–25
six papers selected by
Nikita Dewani, Max Delbrück Centre for Molecular Medicine

Atorvastatin Regulates MALAT1/miR-200c/NRF2 Activity to Protect Against Podocyte Pyroptosis Induced by High Glucose.
Long non-coding RNA NEAT1 promotes lipopolysaccharide-induced injury in human tubule epithelial cells by regulating miR-93-5p/TXNIP axis.
A Glycolysis-Based Long Non-coding RNA Signature Accurately Predicts Prognosis in Renal Carcinoma Patients.
Exosomal lncRNA-p21 derived from mesenchymal stem cells protects epithelial cells during LPS-induced acute lung injury by sponging miR-181.
Mechanism of miR-365 in regulating BDNF-TrkB signal axis of HFD/STZ induced diabetic nephropathy fibrosis and renal function.
Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease.

Diabetes Metab Syndr Obes. 2021 ;14 1631-1645

Atorvastatin Regulates MALAT1/miR-200c/NRF2 Activity to Protect Against Podocyte Pyroptosis Induced by High Glucose.

Yi Zuo, Li Chen, Xiaoyun He, Zhen Ye, Ling Li, Zhanhong Liu, Suxian Zhou.

   Background: Diabetic nephropathy (DN) is one of the main complications of diabetes mellitus (DM), which leads to the long-term loss of kidney functions. Long noncoding RNAs (LncRNAs) can alleviate DN by interacting with microRNAs (miRNAs). In this work, we aimed to explore the effects of the MALAT1/miR-200c/NRF2 regulatory axis on the pyroptosis and oxidative stress (Oxidative stress, OS) of renal podocytes in high glucose (HG) environment and whether the lipid-lowering drug atorvastatin (AT) can relieve renal OS through this approach.
Methods: MPC-5, a mouse podocyte cell line, was induced by HG as a cell model. The protein expressions of caspase-1, GSDMD, NLRP3, NRF2, etc. were detected by Western blotting and immunofluorescence, and the mRNA level of caspase-1, GSDMD, NLRP3, NRF2, MALAT1, miR-200c was tested by qRT-PCR. The cell pyroptosis of podocytes treated with AT was verified by CCK-8 or flow cytometry. The levels of Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured by spectrophotometer, respectively.
Results: The caspase-1 was upregulated in time-dependent manner and got the peak at 48 h and 30 mmol/L respectively in MPC-5 cells treated with HG. Further, the expression of GSDMD, MALAT1 and miR-200c were increased, while the level of NRF2, HO-1, OS-related indicators, were decreased simultaneously. Knockdown the MALAT1 protected MPC-5 cells from pyroptosis and OS induced by HG. However, overexpressing miR-200c in control-group cells increased pyroptosis and upregulated the OS level with HG culture medium. Further, atorvastatin protected MPC-5 cells from cell pyroptosis and downregulated the level of renal OS via attenuating the expression of MALAT1 and miR-200c.
Conclusion: Atorvastatin protects podocyte cells via MALAT1/miR-200c/NRF2 signal pathway from pyroptosis and OS induced by HG.

Keywords:  MALAT1; NRF2; atorvastatin; miR-200c; podocytes; pyroptosis

DOI:  https://doi.org/10.2147/DMSO.S298950
Med Microbiol Immunol. 2021 Apr 22.

Long non-coding RNA NEAT1 promotes lipopolysaccharide-induced injury in human tubule epithelial cells by regulating miR-93-5p/TXNIP axis.

Jing Yang, Lin Wu, Shanshou Liu, Xiaomin Hu, Qianmei Wang, Liying Fang.

  Many long non-coding RNAs (lncRNAs) have been found to play crucial roles in sepsis-induced acute kidney injury (AKI), including lncRNA nuclear-enriched abundant transcript 1 (NEAT1). We aimed to further elucidate the functions and molecular mechanism of NEAT1 in sepsis-induced AKI. Sepsis-induced AKI cell model was established by treatment with lipopolysaccharide (LPS) in human tubule epithelial (HK2) cells. Cell viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. Western blot assay was performed to measure all protein levels. The concentrations of inflammatory factors were evaluated using enzyme-linked immunosorbent assay (ELISA). The expression levels of inflammatory factors, NEAT1, microRNA-93-5p (miR-93-5p), and thioredoxin-interacting protein (TXNIP) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The oxidative stress factors were detected using corresponding kits. The interaction between miR-93-5p and NEAT1 or TXNIP was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. NEAT1 was upregulated in serum of sepsis patients and LPS-induced HK2 cells. NEAT1 silence alleviated LPS-induced HK2 cell injury by inhibiting apoptosis, inflammation and oxidative stress. Moreover, miR-93-5p was a direct target of NEAT1, and suppression of NEAT1 weakened LPS-induced injury by upregulating miR-93-5p in HK2 cells. Furthermore, TXNIP was a downstream target of miR-93-5p, and miR-93-5p attenuated LPS-induced HK2 cell injury by downregulating TXNIP. In addition, NEAT1 regulated TXNIP expression by acting as a sponge of miR-93-5p. NEAT1 might aggravate LPS-induced injury in HK2 cells by regulating miR-93-5p/TXNIP axis, providing a potential therapeutic strategy for sepsis-associated AKI.

Keywords:  Acute kidney injury; NEAT1; Sepsis; TXNIP; miR-93-5p

DOI:  https://doi.org/10.1007/s00430-021-00705-6
Front Genet. 2021 ;12 638980

A Glycolysis-Based Long Non-coding RNA Signature Accurately Predicts Prognosis in Renal Carcinoma Patients.

Honghao Cao, Hang Tong, Junlong Zhu, Chenchen Xie, Zijia Qin, Tinghao Li, Xudong Liu, Weiyang He.

   Background: The prognosis of renal cell carcinoma (RCC) varies greatly among different risk groups, and the traditional indicators have limited effect in the identification of risk grade in patients with RCC. The purpose of our study is to explore a glycolysis-based long non-coding RNAs (lncRNAs) signature and verify its potential clinical significance in prognostic prediction of RCC patients.
Methods: In this study, RNA data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regression displayed six significantly related lncRNAs (AC124854.1, AC078778.1, EMX2OS, DLGAP1-AS2, AC084876.1, and AC026401.3) which were utilized in construction of risk score by a formula. The accuracy of risk score was verified by a series of statistical methods such as receiver operating characteristic (ROC) curves, nomogram and Kaplan-Meier curves. Its potential clinical significance was excavated by gene enrichment analysis.
Results: Kaplan-Meier curves and ROC curves showed reliability of the risk score to predict the prognosis of RCC patients. Stratification analysis indicated that the risk score was independent predictor compare to other traditional clinical parameters. The clinical nomogram showed highly rigorous with index of 0.73 and precisely predicted 1-, 3-, and 5-year survival time of RCC patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) depicted the top ten correlated pathways in both high-risk group and low-risk group. There are 6 lncRNAs and 25 related mRNAs including 36 lncRNA-mRNA links in lncRNA-mRNA co-expression network.
Conclusion: This research demonstrated that glycolysis-based lncRNAs possessed an important value in survival prediction of RCC patients, which would be a potential target for future treatment.

Keywords:  carcinoma; glycolysis; lncRNA; prognosis; renal cell

DOI:  https://doi.org/10.3389/fgene.2021.638980
Acta Biochim Biophys Sin (Shanghai). 2021 Apr 23. pii: gmab043. [Epub ahead of print]

Exosomal lncRNA-p21 derived from mesenchymal stem cells protects epithelial cells during LPS-induced acute lung injury by sponging miR-181.

Xintong Sui, Wei Liu, Zhi Liu.

  Long noncoding RNAs (lncRNAs) act as essential regulators of various diseases. However, the functions of lncRNAs in sepsis-induced acute lung injury (SALI) remain unclear. Here, we found that lipopolysaccharide could upregulate lncRNA-p21 expression in mesenchymal stem cells (MSCs) in a time- and dose-dependent manner and that lncRNA-p21 was packaged into exosomes. Furthermore, we demonstrated that treatment with exosomal lncRNA-p21 could increase the expression of sirtuin 1 (SIRT1) to protect MLE-12 cells from apoptosis during sepsis. Moreover, we identified SIRT1 as a direct target of miR-181 and found that the level of SIRT1 was negatively correlated with the level of miR-181. The luciferase reporter assay also confirmed the negative correlation between the levels of miR-181 and lncRNA-p21. Our results showed that the lncRNA-p21-induced downregulation of miR-181 might suppress epithelial cell apoptosis and alleviate lung tissue injury by upregulating SIRT1 expression, suggesting the potential therapeutic effects of lncRNA-p21 on SALI. In conclusion, we found that the novel lncRNA-p21/miR-181/SIRT1 pathway may play an important role in the progression of SALI, and MSC-derived exosomes may be a new therapeutic strategy for this disease.

Keywords:  SIRT1; acute lung injury; exosomes; lncRNA-p21; miR-181

DOI:  https://doi.org/10.1093/abbs/gmab043
Int Urol Nephrol. 2021 Apr 21.

Mechanism of miR-365 in regulating BDNF-TrkB signal axis of HFD/STZ induced diabetic nephropathy fibrosis and renal function.

Peng Zhao, Xiaqiu Li, Yang Li, Jiaying Zhu, Yu Sun, Jianli Hong.

   PURPOSE: Diabetic nephropathy (DN) is one of the most serious complications of diabetes that leads to decline of renal function. Although numerous studies have revealed that microRNAs (miRNAs) play essential roles in the progression of DN, whether miR-365 is involved remains elusive.
METHODS: The successful construction of DN model was confirmed by ELSIA, hematoxylin-eosin (HE) and Masson staining assay. The expression of miR-365 was detected through RT-qPCR. The levels of BDNF, p-TrkB, α-smooth muscle actin (SMA), collagen IV (Col.IV), transforming growth factor-β1 (TGF-β1), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were evaluated by western blot, IF or ELISA assays. Luciferase reporter assay was used to detect the interaction between miR-365 and BDNF.
RESULTS: The DN mice model was induced by streptozotocin (STZ). Then miR-365 expression was found to upregulate in tissues of DN rat. Furthermore, elevated expression of miR-365 was found in high glucose (HG)-treated HK-2 cells. Silencing of miR-365 suppressed the accumulation of ECM components and secretion of inflammatory cytokines in HK-2 cells. In addition, it was demonstrated that miR-365 could target BDNF. The protein levels of BDNF and p-TrkB were negatively regulated by miR-365 in HK-2 cells. Moreover, inhibition of miR-365 suppressed the levels of SMA, Col.IV, TGF-β1, TNF-α, and IL-6, indicating the renal fibrosis was inhibited by miR-365 knockdown.
CONCLUSION: MiR-365 could regulate BDNF-TrkB signal axis in STZ induced DN fibrosis and renal function. The results of the current study might provide a promising biomarker for the treatment of DN in the future.

Keywords:  BDNF; Diabetic nephropathy; MiR-365; TrkB

DOI:  https://doi.org/10.1007/s11255-021-02853-3
Cell. 2021 Apr 13. pii: S0092-8674(21)00381-0. [Epub ahead of print]

Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease.

GTEx Consortium

  Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.

Keywords:  GTEx; co-expression; colocalization; complex trait; disease; eQTL; expression quantitative trait loci; lncRNA; long non-coding RNA

DOI:  https://doi.org/10.1016/j.cell.2021.03.050