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CD154-CD40 T-cell co-stimulation pathway is a key mechanism in kidney ischemia-reperfusion injury.

ABSTRACT: Ischemia-reperfusion occurs in a great many clinical settings and contributes to organ failure or dysfunction. CD154-CD40 signaling in leukocyte-endothelial cell interactions or T-cell activation facilitates tissue inflammation and injury. Here we tested a siRNA anti-CD40 in rodent warm and cold ischemia models to check the therapeutic efficacy and anti-inflammatory outcome of in vivo gene silencing. In the warm ischemia model different doses were used, resulting in clear renal function improvement and a structural renoprotective effect. Renal ischemia activated the CD40 gene and protein expression, which was inhibited by intravenous siRNA administration. CD40 gene silencing improved renal inflammatory status, as seen by the reduction of CD68 and CD3 T-cell infiltrates, attenuated pro-inflammatory, and enhanced anti-inflammatory mediators. Furthermore, siRNA administration decreased a spleen pro-inflammatory monocyte subset and reduced TNF? secretion by splenic T cells. In the cold ischemia model with syngeneic and allogeneic renal transplantation, the most effective dose induced similar functional and structural renoprotective effects. Our data show the efficacy of our siRNA in modulating both the local and the systemic inflammatory milieu after an ischemic insult. Thus, CD40 silencing could emerge as a novel therapeutic strategy in solid organ transplantation.

SUBMITTER: de Ramon L

PROVIDER: S-EPMC4558568 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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CD154-CD40 T-cell co-stimulation pathway is a key mechanism in kidney ischemia-reperfusion injury.

de Ramon Laura L Ripoll Elia E Merino Ana A Lúcia Marc M Aran Josep M JM Pérez-Rentero S S Lloberas Nuria N Cruzado Josep M JM Grinyó Josep M JM Torras Juan J

Kidney international 20150520 3

Ischemia-reperfusion occurs in a great many clinical settings and contributes to organ failure or dysfunction. CD154-CD40 signaling in leukocyte-endothelial cell interactions or T-cell activation facilitates tissue inflammation and injury. Here we tested a siRNA anti-CD40 in rodent warm and cold ischemia models to check the therapeutic efficacy and anti-inflammatory outcome of in vivo gene silencing. In the warm ischemia model different doses were used, resulting in clear renal function improvem ...[more]

PMID: 25993320

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Project description:Spinal cord ischemia-reperfusion injury (SCII) is a pathological process with severe complications such as paraplegia and paralysis. Aberrant miRNA expression is involved in the development of SCII. Differences in the experimenters, filtering conditions, control selection, and sequencing platform may lead to different miRNA expression results. This study systematically analyzes the available SCII miRNA expression data to explore the key differently expressed miRNAs (DEmiRNAs) and the underlying molecular mechanism in SCII. A systematic bioinformatics analysis was performed on 23 representative rat SCII miRNA datasets from PubMed. The target genes of key DEmiRNAs were predicted on miRDB. The DAVID and TFactS databases were utilized for functional enrichment and transcription factor binding analyses. In this study, 19 key DEmiRNAs involved in SCII were identified, 9 of which were upregulated (miR-144-3p, miR-3568, miR-204, miR-30c, miR-34c-3p, miR-155-3p, miR-200b, miR-463, and miR-760-5p) and 10 downregulated (miR-28-5p, miR-21-5p, miR-702-3p, miR-291a-3p, miR-199a-3p, miR-352, miR-743b-3p, miR-125b-2-3p, miR-129-1-3p, and miR-136). KEGG enrichment analysis on the target genes of the upregulated DEmiRNAs revealed that the involved pathways were mainly the cGMP-PKG and cAMP signaling pathways. KEGG enrichment analysis on the target genes of the downregulated DEmiRNAs revealed that the involved pathways were mainly the Chemokine and MAPK signaling pathways. GO enrichment analysis indicated that the target genes of the upregulated DEmiRNAs were markedly enriched in biological processes such as brain development and the positive regulation of transcription from RNA polymerase II promoter. Target genes of the downregulated DEmiRNAs were mainly enriched in biological processes such as intracellular signal transduction and negative regulation of cell proliferation. According to the transcription factor analysis, the four transcription factors, including SP1, GLI1, GLI2, and FOXO3, had important regulatory effects on the target genes of the key DEmiRNAs. Among the upregulated DEmiRNAs, miR-3568 was especially interesting. While SCII causes severe neurological deficits of lower extremities, the anti-miRNA oligonucleotides (AMOs) of miR-3568 improve neurological function. Cleaved caspase-3 and Bax was markedly upregulated in SCII comparing to the sham group, and miR-3568 AMO reduced the upregulation. Bcl-2 expression levels showed a opposite trend as cleaved caspase-3. The expression of GATA6, GATA4, and RBPJ decreased after SCII and miR-3568 AMO attenuated this upregulation. In conclusion, 19 significant DEmiRNAs in the pathogenesis of SCII were identified, and the underlying molecular mechanisms were validated. The DEmiRNAs could serve as potential intervention targets for SCII. Moreover, inhibition of miR-3568 preserved hind limb function after SCII by reducing apoptosis, possibly through regulating GATA6, GATA4, and RBPJ in SCII.

Dataset Information

CD154-CD40 T-cell co-stimulation pathway is a key mechanism in kidney ischemia-reperfusion injury.

Publications

CD154-CD40 T-cell co-stimulation pathway is a key mechanism in kidney ischemia-reperfusion injury.

Similar Datasets

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