bims-lorfki Biomed News
on Long non-coding RNA functions in the kidney
Issue of 2021‒06‒06
eight papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

  1. J Bioenerg Biomembr. 2021 Jun 02.
      Inflammation and renal cell apoptosis participate in sepsis-induced acute kidney injury. Previous research found the upregulation of long non-coding RNA Linc-KIAA1737-2 in hypoxia- or inflammation-challenged human proximal tubular epithelial cells, but its role in sepsis-induced acute kidney injury is underexplored. In this research, we found that Linc-KIAA1737-2 could be upregulated in HK-2 human proximal tubular epithelial cells by LPS treatment, and knock-down of this lncRNA significantly attenuated LPS-induced apoptosis in HK-2 cells, while its overexpression showed opposite effect. MiR-27a-3p was confirmed to interact with Linc-KIAA1737-2 in HK-2 cells by RNA pull-down and dual-luciferase assay. MiR-27a-3p mimic transfection significantly attenuated LPS-induced HK-2 cell apoptosis by downregulating the protein levels of TLR4 and NF-κB, which was overturned by overexpression of Linc-KIAA1737-2. Our results suggested that Linc-KIAA1737-2 could promote LPS-induced apoptosis in HK-2 cells, and presumably sepsis-induced acute kidney injury, by regulating the miR-27a-3p/TLR4/NF-κB axis.
    Keywords:  Acute kidney injury; Linc-KIAA1737–2; NF-κB; Sepsis; TLR4; miR-27a
  2. Front Physiol. 2021 ;12 684236
      Renal fibrosis is one of the most characterized pathological features in chronic kidney disease (CKD). Progressive fibrosis eventually leads to renal failure, leaving dialysis or allograft transplantation the only clinical option for CKD patients. Transforming growth factor-β (TGF-β) is the key mediator in renal fibrosis and is an essential regulator for renal inflammation. Therefore, the general blockade of the pro-fibrotic TGF-β may reduce fibrosis but may risk promoting renal inflammation and other side effects due to the diverse role of TGF-β in kidney diseases. Long non-coding RNAs (lncRNAs) are RNA transcripts with more than 200 nucleotides and have been regarded as promising therapeutic targets for many diseases. This review focuses on the importance of TGF-β and lncRNAs in renal inflammation, fibrogenesis, and the potential applications of TGF-β and lncRNAs as the therapeutic targets and biomarkers in renal fibrosis and CKD are highlighted.
    Keywords:  SMADs; TGF-β; inflammation; long non-coding RNA; molecular therapy; renal fibrosis
  3. Int Urol Nephrol. 2021 Jun 05.
      BACKGROUND: Long noncoding RNA PVT1 is associated with diverse human diseases, including acute kidney injury (AKI). However, our understandings of PVT1 on septic AKI are limited.METHODS: The septic AKI model was constructed through lipopolysaccharide (LPS) treatment. PVT1 and miR-17-5p levels were measured using qRT-PCR analysis. The concentrations of inflammatory cytokines were determined with ELISA kits. Cell viability and apoptosis were assessed using CCK-8 assay and flow-cytometric analysis, respectively. Protein levels were examined using western blot assay. The targeting association between miR-17-5p and PVT1 was verified by dual-luciferase reporter, RIP and RNA pull-down assays.
    RESULTS: PVT1 level was elevated and miR-17-5p level was declined in septic AKI patients' serum and LPS-stimulated HK-2 cells. Cell viability was suppressed and cell apoptosis and inflammation were promoted after LPS treatment. PVT1 knockdown or miR-17-5p elevation restored LPS-mediated HK-2 cell injury. MiR-17-5p was sponged by PVT1, and its inhibition weakened the impact of PVT1 deficiency on LPS-mediated injury of HK-2 cells. In addition, PVT1 knockdown inactivated NF-κB pathway mediated by LPS treatment, but miR-17-5p inhibition further reversed this effect.
    CONCLUSION: PVT1 knockdown promoted cell viability, suppressed inflammatory response and apoptosis by regulating miR-17-5p expression and NF-κB pathway in LPS-stimulated HK-2 cells.
    Keywords:  LPS; NF-κB; PVT1; Septic AKI; miR-17-5p
  4. J Cell Mol Med. 2021 Jun;25(11): 4922-4937
      Long non-coding RNA (lncRNA) lnc-ISG20 has been found aberrantly up-regulated in the glomerular in the patients with diabetic nephropathy (DN). We aimed to elucidate the function and regulatory mechanism of lncRNA lnc-ISG20 on DN-induced renal fibrosis. Expression patterns of lnc-ISG20 in kidney tissues of DN patients were determined by RT-qPCR. Mouse models of DN were constructed, while MCs were cultured under normal glucose (NG)/high glucose (HG) conditions. The expression patterns of fibrosis marker proteins collagen IV, fibronectin and TGF-β1 were measured with Western blot assay. In addition, the relationship among lnc-ISG20, miR-486-5p, NFAT5 and AKT were analysed using dual-luciferase reporter assay and RNA immunoprecipitation. The effect of lnc-ISG20 and miR-486/NFAT5/p-AKT axis on DN-associated renal fibrosis was also verified by means of rescue experiments. The expression levels of lnc-ISG20 were increased in DN patients, DN mouse kidney tissues and HG-treated MCs. Lnc-ISG20 silencing alleviated HG-induced fibrosis in MCs and delayed renal fibrosis in DN mice. Mechanistically, miR-486-5p was found to be a downstream miRNA of lnc-ISG20, while miR-486-5p inhibited the expression of NFAT5 by binding to its 3'UTR. NFAT5 overexpression aggravated HG-induced fibrosis by stimulating AKT phosphorylation. However, NFAT5 silencing reversed the promotion of in vitro and in vivo fibrosis caused by lnc-ISG20 overexpression. Our collective findings indicate that lnc-ISG20 promotes the renal fibrosis process in DN by activating AKT through the miR-486-5p/NFAT5 axis. High-expression levels of lnc-ISG20 may be a useful indicator for DN.
    Keywords:  AKT; Lnc-ISG20; MicroRNA-486-5p; NFAT5; diabetic nephropathy; fibrosis
  5. Medicine (Baltimore). 2021 Jun 04. 100(22): e26062
      ABSTRACT: Diabetic kidney disease (DKD) has become the major contributor to end-stage renal disease with high incidence and mortality. The functional roles and exact mechanisms of long noncoding RNA (lncRNA)-associated competing endogenous RNA (ceRNA) network in DKD are still largely unknown. This study sought to discover novel potential biomarkers and ceRNA network for DKD.The candidate differentially expressed genes (DEGs), lncRNAs and microRNAs (miRNAs) in human glomerular and tubular tissues derived from Gene Expression Omnibus database were systematically selected and analyzed. Functional enrichment analysis and protein-protein interaction network analysis were conducted to identify hub genes and reveal their regulatory mechanisms involved in DKD. Following this, the integrated ceRNA network was constructed by bioinformatics methods.A total of 164 DEGs, 6 lncRNAs and 18 miRNAs correlated with DKD were finally filtered and identified. It is noteworthy that the global lncRNA-associated ceRNA network related to DKD was constructed, among which lnc-HIST2H2AA4-1, VCAN-AS1 and MAGI2-AS1 were identified as the 3 key lncRNAs, and VCAN, FN1, CCL2, and KNG1 were identified as the predominant genes. Consistent with that observed in the training set, 3 of the key genes also showed significant differences in the 2 validation datasets. Integrating with functional enrichment analysis results, these key genes in the ceRNA network were mainly enriched in the immune and inflammation-related pathways.This study first identified key lncRNAs, miRNAs and their targets, and further revealed a global view of lncRNA-associated ceRNA network involved in DKD by using whole gene transcripts analysis.
  6. J Leukoc Biol. 2021 Jun 01.
      Diabetic nephropathy (DN) is a leading cause of end-stage renal failure. The study aimed to investigate whether long noncoding RNA taurine-upregulated gene 1 (TUG1) can ameliorate the endoplasmic reticulum stress (ERS) and apoptosis of renal tubular epithelial cells in DN, and the underlying mechanism. The DN mouse model was established by streptozocin injection, and the human renal tubular epithelial cell line HK-2 was treated with high glucose (HG) to mimic DN in vitro. The molecular mechanism was explored through dual-luciferase activity assay, RNA pull-down assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (CHIP) assay. The expression of TUG1 was significantly decreased in the renal tubules of DN model mice. Overexpression of TUG1 reduced the levels of ERS markers and apoptosis markers by inhibiting reticulon-1 (RTN1) expression in HG-induced HK-2 cells. Furthermore, TUG1 down-regulated RTN1 expression by inhibiting the binding of transcription factor PU.1 to the RTN1 promoter, thereby reducing the levels of ERS markers and apoptosis markers. Meanwhile, TUG1-overexpression adenovirus plasmids injection significantly alleviated tubular lesions, and reduced RTN1 expression, ERS markers and apoptosis markers, whereas these results were reversed by injection of PU.1-overexpression adenovirus plasmids. TUG1 restrains the ERS and apoptosis of renal tubular epithelial cells and ameliorates DN through inhibition of transcription factor PU.1.
    Keywords:  PU.1; RTN1; TUG1; diabetic nephropathy; endoplasmic reticulum stress
  7. Drug Des Devel Ther. 2021 ;15 2229-2242
      Objective: Total glucosides of paeony (TGP) has been proven to affect anti-inflammatory, immunomodulatory and hypoxia tolerance. This study investigates the effect of TGP on autophagy in acute kidney injury (AKI) induced by ischemia-reperfusion (I/R).Methods: Rat model of AKI induced by I/R was established. Rats were administered with TGP at different doses by oral gavage. The contents of BUN, creatinine, NGAL, Kim-1 and IL-18 were detected. The levels of inflammatory factors (TNF-α, IL-1β and IL-6) and autophagy were measured. The expressions of lncRNA TUG1, miR-29a and PTEN were detected and their binding relationships were verified. I/R rat model with overexpressed TUG1 was established to explore the effect of TGP on kidney injury and autophagy. The hypoxia/reoxygenation (HR) model of HK-2 cells and the HR model of HK-2 cells overexpressing TUG1 and low-expressing PTEN were established.
    Results: TGP decreased the contents of BUN, creatinine, NGAL, Kim-1 and IL-18, and reduced the levels of inflammatory factors. LncRNA TUG1 and PTEN were downregulated, and miR-29a was upregulated in kidney tissues. The binding relationships between lncRNA TUG1 and miR-29a, and miR-29a and PTEN were confirmed. TGP suppressed PTEN expression via the lncRNA TUG1/miR-29a axis. Overexpressing lncRNA TUG1 attenuated the protective effect of TGP on AKI and autophagy in HK-2 cells. TGP improved cell viability and inhibited the autophagy in HR model of HK-2 cells via lncRNA TUG1/miR-29a/PTEN axis.
    Conclusion: TGP inhibited autophagy and improved AKI induced by I/R via the lncRNA TUG1/miR-29a/PTEN axis.
    Keywords:  acute kidney injury; autophagy; ischemia-reperfusion; lncRNA TUG1/miR-29a/PTEN; total glucosides of paeony
  8. Exp Ther Med. 2021 Jul;22(1): 739
      Long non-coding RNAs (lncRNAs) have been identified as a class of regulatory RNAs that participate in both physiological and pathological conditions, including acute kidney injury. However, the roles of lncRNA dysregulation in the pathogenesis of contrast-induced acute kidney injury (CI-AKI) are largely unknown. In the present study, the expression profiles of lncRNAs in kidney tissue were compared between rats with CI-AKI and controls using high-throughput RNA sequencing. In total, 910 differentially expressed (DE) lncRNAs (DElncRNAs), including 415 downregulated and 495 upregulated lncRNAs, were identified at 12 h after intra-arterial iodinated contrast medium injection (fold change ≥2; P<0.05). Eight DElncRNAs were further selected and validated using reverse transcription-quantitative polymerase chain reaction. A previous study defined microRNA (miRNA) and mRNA expression changes in the same CI-AKI model. In the present study, a lncRNA-mRNA co-expression network comprising 349 DElncRNAs and 202 DEmRNAs was constructed. The function of these DElncRNAs was mainly associated with oxidative stress and inflammation. Additionally, lncRNA-associated competing endogenous RNA (ceRNA) analysis revealed a network comprising 40 DElncRNA nodes, 5 DEmiRNA nodes and 59 DEmRNA nodes. Among which, the carnosine dipeptidase 1-specific and the transmembrane protein 184B-specific networks were likely to be associated with CI-AKI. The results of the present study revealed the expression profile and potential roles of lncRNAs in CI-AKI, and provide a framework for further mechanistic studies.
    Keywords:  RNA sequencing; co-expression analysis; competing endogenous RNA; contrast-induced acute kidney injury; long non-coding RNA