Dataset Information

LncRNA expression character associated with ischemic reperfusion injury.

ABSTRACT: Ischemic reperfusion injury (IRI) contributes to morbidity and mortality worldwide and results in a poor outcome for patients suffering from myocardial infarction. Ischemic post?conditioning (IPostC), consisting of one or several brief periods of ischemia and reperfusion, generates powerful protection against IRI. The mechanism of IPostC initiation and development has previously been investigated, however still remains to be fully elucidated. Notably, long non?coding (lnc) RNAs have previously been demonstrated to be important in cardiovascular diseases. However, there is little information about the systematic analysis of IRI?associated lncRNA expression signature. The present study used microarrays to analyze the lncRNA expression characters of ischemic IPostc (corresponding to IRI), and demonstrated that 2,292 lncRNAs were observed to be upregulated and 1,848 lncRNAs downregulated. Gene ontology (GO) and Pathway analysis subsequently demonstrated that dysregulated lncRNAs participated in various biological processes, which are upregulated or downregulated in IPostC tissues. Finally, the present study verified that AK144818, ENS?MUS?T00000156637, ENS?MUS?T00000118342, ENS?MUS?T00000118149, uc008ane.1, ENS?MUS?T00000164933, ENS?MUS?T00000162347, ENS?MUS?T00000135945, and ENS?MUS?T00000176338, ENS?MUST00000120587, END?MUST00000155271, ENS?MUS?T00000125121 and Uc008thl.1 were associated with the initiation and development of IPostC. The present study may aid in the understanding of the initiation and development mechanisms of IPostC and provide novel and potential biomarkers that may be used in the diagnosis or as therapeutic targets in the treatment of IRI.

SUBMITTER: Wu X

PROVIDER: S-EPMC5646951 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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lncRNA expression character associated with ischemic reperfusion injury.

Wu Xiaowei X Zhu Hongyi H Zhu Suhua S Hao Maojuan M Li Qingping Q

Molecular medicine reports 20170721 4

Ischemic reperfusion injury (IRI) contributes to morbidity and mortality worldwide and results in a poor outcome for patients suffering from myocardial infarction. Ischemic post‑conditioning (IPostC), consisting of one or several brief periods of ischemia and reperfusion, generates powerful protection against IRI. The mechanism of IPostC initiation and development has previously been investigated, however still remains to be fully elucidated. Notably, long non‑coding (lnc) RNAs have previously b ...[more]

PMID: 28731128

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Project description:Acute kidney injury (AKI) is associated with an abrupt loss of kidney function that results in significant morbidity and mortality. Considerable effort has focused around the identification of diagnostic biomarkers and the analysis of molecular events. Most studies have adopted organ-wide approaches that do not fully capture the interplay among different cell types in the pathophysiology of AKI. To extend our understanding of molecular and cellular events in AKI, we developed a mouse line that enables the identification of translational profiles in specific cell types by CRE recombinase-dependent activation of an eGFP-tagged L10a ribosomal protein subunit, and consequently, translating ribosome affinity purification (TRAP) of mRNA populations. By utilizing cell-type specific CRE-driver lines, in this study we identify distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Cell-specific translational expression profiles were uncovered 24 hours after IRI from four populations enriched for distinct anatomical and cellular subgroups: nephron, interstitial cell populations, vascular endothelium, and macrophages/monocytes by Affymetrix microarray. A construct containing the CAGGS promoter driving eGFP-L10a, with a loxP-site flanked triple SV40 polyA cassette between promoter and eGFP-L10a cassette was targeted into the ubiquitously active Rosa26 locus. The upstream polyA cassette is designed to block activity of the downstream eGFP-L10a cassette. CRE-dependent removal of this transcriptional block activates eGFP::L10a production within the CRE-producing cell, and all of its descendants. Mice carrying the conditional eGFP-L10a allele, referred to as L10a, were maintained in a homozygous state. L10a mice were crossed to four CRE strains to activate eGFP::L10a expression in four predominantly non-overlapping cellular compartments in the kidney. A Six2-Tet-GFP::CRE allele is active exclusively within nephron progenitors; consequently, historical labeling results in eGFP::L10a expression throughout the main body of the nephron. A Foxd1-GFP::CRE allele is active in the progenitors of many of the interstitial cell lineages including those generating mesangial and non-glomerular pericytes. In addition, Foxd1 is normally expressed in podocytes. Cdh5-CRE is reported to be active throughout the vascular endothelium, and finally, Lyz2-CRE specifically labels cells of the myeloid lineage, notably macrophages, monocytes and dendritic cells. Mice carrying any CRE allele and the L10a allele are designated generically CRE-L10a. six2-L10a, foxd1-L10a, cdh5-L10a and lyz2-L10a denote specifically mice that are compound heterozygotes for the indicated CRE driver and L10a. CRE-L10a, L10a heterozygous littermates without CRE allele, C57BL/6 wild type mice were subjected to renal bilateral warm ischemia 28 minutes followed by 24-hour reperfusion when the kidney TRAP RNA and total RNA were isolated and subjected to Affymetrix microarray. Biological triplicates for each CRE-L10a line underwent no Surgery; sham Surgery and IRI treatment.

Project description:BackgroundThe mitochondria and endoplasmic reticulum (ER) communicate via contact sites known as mitochondria associated membranes (MAMs). Many important cellular functions such as bioenergetics, mitophagy, apoptosis, and calcium signaling are regulated by MAMs, which are thought to be closely related to ischemic reperfusion injury (IRI). However, there exists a gap in systematic proteomic research addressing the relationship between these cellular processes.MethodsA 4D label free mass spectrometry-based proteomic analysis of mitochondria associated membranes (MAMs) from the human renal proximal tubular epithelial cell line (HK-2 cells) was conducted under both normal (N) and hypoxia/reperfusion (HR) conditions. Subsequent differential proteins analysis aimed to characterize disease-relevant signaling molecules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was applied to total proteins and differentially expressed proteins, encompassing Biological Process (BP), Cell Component (CC), Molecular Function (MF), and KEGG pathways. Further, Protein-Protein Interaction Network (PPI) exploration was carried out, leading to the identification of hub genes from differentially expressed proteins. Notably, Mitofusion 2 (MFN2) and BCL2/Adenovirus E1B 19-kDa interacting protein 3(BNIP3) were identified and subsequently validated both in vitro and in vivo. Finally, the impact of MFN2 on MAMs during hypoxia/reoxygenation was explored through regulation of gene expression. Subsequently, a comparative proteomics analysis was conducted between OE-MFN2 and normal HK-2 cells, providing further insights into the underlying mechanisms.ResultsA total of 4489 proteins were identified, with 3531 successfully quantified. GO/KEGG analysis revealed that MAM proteins were primarily associated with mitochondrial function and energy metabolism. Differential analysis between the two groups showed that 688 proteins in HR HK-2 cells exhibited significant changes in expression level with P-value < 0.05 and HR/N > 1.5 or HR/N < 0.66 set as the threshold criteria. Enrichment analysis of differentially expressed proteins unveiled biological processes such as mRNA splicing, apoptosis regulation, and cell division, while molecular functions were predominantly associated with energy metabolic activity. These proteins play key roles in the cellular responses during HR, offering insights into the IRI mechanisms and potential therapeutic targets. The validation of hub genes MFN2 and BNIP3 both in vitro and vivo was consistent with the proteomic findings. MFN2 demonstrated a protective role in maintaining the integrity of mitochondria associated membranes (MAMs) and mitigating mitochondrial damage following hypoxia/reoxygenation injury, this protective effect may be associated with the activation of the PI3K/AKT pathway.ConclusionsThe proteins located in mitochondria associated membranes (MAMs) are implicated in crucial roles during renal ischemic reperfusion injury (IRI), with MFN2 playing a pivotal regulatory role in this context.

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LncRNA expression character associated with ischemic reperfusion injury.

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lncRNA expression character associated with ischemic reperfusion injury.

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