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Time-Dependent miRNA Profile during Septic Acute Kidney Injury in Mice.

ABSTRACT: (1) Background: Lipopolysaccharide (LPS)-induced systemic inflammation is associated with septic acute kidney injury (AKI). We investigated the time-dependent miRNA expression changes in the kidney caused by LPS. (2) Methods: Male outbred NMRI mice were injected with LPS and sacrificed at 1.5 and 6 h (40 mg/kg i.p., early phase, EP) or at 24 and 48 h (10 mg/kg i.p., late phase, LP). The miRNA profile was established using miRCURY LNA™ microarray and confirmed with qPCR. Total renal proteome was analyzed by LC-MS/MS (ProteomeXchange: PXD014664). (3) Results: Septic AKI was confirmed by increases in plasma urea concentration and in renal TNF-? and IL-6 mRNA expression. Most miRNAs were altered at 6 and 24 h and declined by 48 h. In EP miR-762 was newly identified and validated and was the most elevated miRNA. The predicted target of miR-762, Ras related GTPase 1B (Sar1b) was downregulated. In LP miR-21a-5p was the most influenced miRNA followed by miR-451a, miR-144-3p, and miR-146a-5p. Among the potential protein targets of the most influenced miRNAs, only aquaporin-1, a target of miR-144-3p was downregulated at 24 h. (4) Conclusion: Besides already known miRNAs, septic AKI upregulated miR-762, which may regulate GTP signaling, and miR-144-3p and downregulated its target, aquaporin-1.

SUBMITTER: Tod P

PROVIDER: S-EPMC7432314 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Time-Dependent miRNA Profile during Septic Acute Kidney Injury in Mice.

Tod Pál P Róka Beáta B Kaucsár Tamás T Szatmári Krisztina K Vizovišek Matej M Vidmar Robert R Fonovič Marko M Szénási Gábor G Hamar Péter P

International journal of molecular sciences 20200727 15

(1) Background: Lipopolysaccharide (LPS)-induced systemic inflammation is associated with septic acute kidney injury (AKI). We investigated the time-dependent miRNA expression changes in the kidney caused by LPS. (2) Methods: Male outbred NMRI mice were injected with LPS and sacrificed at 1.5 and 6 h (40 mg/kg i.p., early phase, EP) or at 24 and 48 h (10 mg/kg i.p., late phase, LP). The miRNA profile was established using miRCURY LNA™ microarray and confirmed with qPCR. Total renal proteome was ...[more]

PMID: 32727087

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Project description:BackgroundSeptic acute kidney injury (S-AKI) results from an imbalance in the regulation of systemic inflammatory responses. Glycosylation plays an important role in inflammatory responses. However, the relationship between S-AKI and glycosylation is unclear.MethodsThe datasets of the public platform were analyzed using R language to obtain glycosylation-related differentially expressed genes (GRDEGs) in S-AKI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed for GRDEGs. Hub genes were obtained using three machine learning algorithms and their diagnostic values were evaluated using receiver operating characteristic (ROC) curves. The relationships between the hub genes, immune cells, and signaling pathways were analyzed, and the upstream miRNAs, transcription factors, and compounds of the hub genes were predicted. Mouse models of AKI with sepsis were constructed and the expression of the hub genes was verified.ResultsWe obtained 45 GRDEGs that were mainly enriched in glycoprotein metabolism and immune inflammatory response, such as "O-glycan biosynthesis", "phagosome", "pathogenic Escherichia coli infection", "glycosyltransferase activity", etc. Seven hub genes that have potential diagnostic value were identified and were associated with the regulation of immune cells. Through gene set enrichment analysis (GSEA) of hub genes, it was found that these genes may be involved in metabolism, signaling transduction, and inflammation-related signaling pathways, such as "metabolism of amino and derivatives", "RHO GTPase cycle", "transport of small molecules", "neutrophil degranulation", "immune system", etc. We then predicted 100 miRNAs, 60 TFs, and 23 compounds of the hub genes using forecasting tools. Finally, animal experiments confirmed the differential expression of ASGR1, UMOD, SPTBN1, and ADAMTS17.ConclusionThis study identified and validated four biomarkers associated with abnormal glycosylation that could be potential targets for AKI in sepsis.

Project description:The relationship between cardiac output and septic acute kidney injury (AKI) remains unclear. The purpose of this study was to assess the association between the cardiac index (CI) and the renal outcomes in patients with septic shock.A one-year prospective cohort study was performed in the surgical and medical ICU of a teaching hospital in Nanjing, China. Twenty-nine septic shock patients who required early goal-directed fluid resuscitation were consecutively included. Pulse indicator continuous cardiac output (PiCCO) device was used to measure hemodynamic parameters before and after early goal-directed therapy (EGDT). Based on CI changes after EGDT, patients were assign to the CI increased group or the CI constant group, respectively. The incidence of poor renal outcome, which was defined as AKI on admission without recovery in following three days or new onset AKI within 28 days, was recorded. We investigated whether an increased CI was associated with a better renal outcome.After EGDT, there were 16 patients in the CI increased group and 13 patients in the CI constant group. The incidence of poor renal outcome was lower in CI increased group than in the CI constant group (6% vs. 62%; P?=?0.003) with a relative risk of 0.10. The logistic regression showed that the CI percent change was associated with renal outcome, with an odd ratio of 0.003 (P?=?0.056) after adjustment of possible confounding factors. The CI percent change would predict a good renal outcome (AU ROC 0.739, P?=?0.012) with moderate accuracy (sensitivity 75% and specificity 89%) when using a 10% cut-off value from Youden index. The CI percent change was also positively correlated with creatinine clearance (CCr) after EGDT (??=?0.548; P?=?0.002).The increased CI after EGDT was a protective factor for kidney in patients with septic shock. A CI increased above 10% could be potentially used to predict development and reversibility of AKI in septic shock patients.Clinicaltrials.gov:NCT01862588 (May 13, 2013).

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Time-Dependent miRNA Profile during Septic Acute Kidney Injury in Mice.

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Time-Dependent miRNA Profile during Septic Acute Kidney Injury in Mice.

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