Circular RNA TLK1 Promotes Sepsis-Associated Acute Kidney Injury by Regulating Inflammation and Oxidative Stress Through miR-106a-5p/HMGB1 Axis

Sepsis is an inflammatory disorder and leads to severe acute kidney injury (AKI). Circular RNAs (circRNAs) have been identified as a critical type of regulatory noncoding RNAs (ncRNAs) that present the important functions in various diseases. In this study, we identified a novel circRNA circTLK1 in the regulation of sepsis-induced AKI. We observed that circTLK1 expression was elevated in the cecal ligation and puncture (CLP) rat model compared with that in the control rats. The urine levels of neutrophil gelatinase–associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) and the serum levels of creatinine (sCr) and blood urea nitrogen (BUN) were increased by the CLP treatment in the rats but were blocked by the circTLK1 shRNA. The circTLK1 shRNA reduced the CLP-induced kidney injury in the rats. The circTLK1 knockdown repressed oxidation stress, inflammation, and apoptosis in the sepsis-related AKI rat model. Moreover, lipopolysaccharide (LPS) treatment increased the production of TNF-α, IL-1β, and IL-6 in the HK-2 cells, while the circTLK1 shRNA could attenuate the enhancement in the cells. Bax and cleaved caspase-3 expression was upregulated, but Bcl-2 expression was downregulated by the LPS in the HK-2 cells, in which circTLK1 depletion reversed this effect in the cells. The depletion of circTLK1 attenuated the LPS-induced apoptosis in the HK-2 cells. CircTLK1 enhanced HMGB1 expression by sponging miR-106a-5p in the HK-2 cells, and miR-106a-5p and HMGB1 were involved in circTLK1-meidated injury of LPS-treated cells. Therefore, we concluded that circTLK1 contributed to sepsis-associated AKI by regulating inflammation and oxidative stress through the miR-106a-5p/HMGB1 axis. CircTLK1 and miR-106a-5p may be employed as the potential targets for the treatment of AKI.

[1]  Wenxin Xu,et al.  Circular RNA circ_0068,888 protects against lipopolysaccharide-induced HK-2 cell injury via sponging microRNA-21-5p. , 2021, Biochemical and biophysical research communications.

[2]  Yujie Wang,et al.  miR-106a-5p Functions as a Tumor Suppressor by Targeting VEGFA in Renal Cell Carcinoma , 2020, Disease markers.

[3]  Xin Huang,et al.  miR-129-5p alleviates LPS-induced acute kidney injury via targeting HMGB1/TLRs/NF-kappaB pathway. , 2020, International immunopharmacology.

[4]  P. Xing,et al.  Paclitaxel alleviates the sepsis-induced acute kidney injury via lnc-MALAT1/miR-370-3p/HMGB1 axis. , 2020, Life sciences.

[5]  Yan Shi,et al.  Circular RNA VMA21 ameliorates sepsis‐associated acute kidney injury by regulating miR‐9‐3p/SMG1/inflammation axis and oxidative stress , 2020, Journal of cellular and molecular medicine.

[6]  Kai Wang,et al.  miR-128-3p Inhibits NRP1 Expression and Promotes Inflammatory Response to Acute Kidney Injury in Sepsis , 2020, Inflammation.

[7]  Yu-Fang Song,et al.  The circular RNA TLK1 exacerbates myocardial ischemia/reperfusion injury via targeting miR-214/RIPK1 through TNF signaling pathway. , 2020, Free radical biology & medicine.

[8]  Luwen Wang,et al.  TNF‐α/HMGB1 inflammation signalling pathway regulates pyroptosis during liver failure and acute kidney injury , 2020, Cell proliferation.

[9]  Ling Lin,et al.  Downregulation of microRNA-106a-5p alleviates ox-LDL-mediated endothelial cell injury by targeting STAT3 , 2020, Molecular medicine reports.

[10]  Xiaofeng Shi,et al.  CircPRKCI relieves lipopolysaccharide-induced HK2 cell injury by upregulating the expression of miR-545 target gene ZEB2. , 2020, BioFactors.

[11]  Zhen Ma,et al.  Long noncoding RNA HOXA‐AS2 mediates microRNA‐106b‐5p to repress sepsis‐engendered acute kidney injury , 2020, Journal of biochemical and molecular toxicology.

[12]  Bin Wang,et al.  Long Noncoding RNA DANCR Suppressed Lipopolysaccharide-Induced Septic Acute Kidney Injury by Regulating miR-214 in HK-2 Cells , 2020, Medical science monitor : international medical journal of experimental and clinical research.

[13]  Z. Wang,et al.  Transcriptome sequencing of circular RNA reveals a novel circular RNA-has_circ_0114427 in the regulation of inflammation in acute kidney injury. , 2020, Clinical science.

[14]  John H. Zhang,et al.  Circular RNA TLK1 Aggravates Neuronal Injury and Neurological Deficits after Ischemic Stroke via miR-335-3p/TIPARP , 2019, The Journal of Neuroscience.

[15]  Yunyan Jing,et al.  MiR-106a aggravates sepsis-induced acute kidney injury by targeting THBS2 in mice model 1 , 2019, Acta cirurgica brasileira.

[16]  Bin Wang,et al.  Exosomal miRNA-19b-3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury , 2019, Cell Death & Differentiation.

[17]  Chunbo Chen,et al.  Circular RNA involved in the protective effect of losartan on ischemia and reperfusion induced acute kidney injury in rat model. , 2019, American journal of translational research.

[18]  J. Koyner,et al.  Sepsis associated acute kidney injury , 2019, British Medical Journal.

[19]  Yi Fang,et al.  Delayed Remote Ischemic Preconditioning ConfersRenoprotection against Septic Acute Kidney Injury via Exosomal miR-21 , 2019, Theranostics.

[20]  Zhongqing Chen,et al.  SIRT1-mediated HMGB1 deacetylation suppresses sepsis-associated acute kidney injury. , 2019, American journal of physiology. Renal physiology.

[21]  M. van Meurs,et al.  Kidney histopathology in lethal human sepsis , 2018, Critical Care.

[22]  Simon C Watkins,et al.  The Endotoxin Delivery Protein HMGB1 Mediates Caspase‐11‐Dependent Lethality in Sepsis , 2018, Immunity.

[23]  M. Levy,et al.  Sepsis and septic shock , 2018, The Lancet.

[24]  Yi Chen,et al.  Long non‐coding RNA NEAT1 plays an important role in sepsis‐induced acute kidney injury by targeting miR‐204 and modulating the NF‐&kgr;B pathway , 2018, International immunopharmacology.

[25]  G. Regolisti,et al.  Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury , 2018, Journal of Nephrology.

[26]  Matthew J. Maiden,et al.  Acute kidney injury in sepsis , 2017, Intensive Care Medicine.

[27]  J. Faix Biomarkers of sepsis , 2013, Critical reviews in clinical laboratory sciences.