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Thrombospondin-1 activation of signal-regulatory protein-? stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.

ABSTRACT: Ischemia reperfusion injury (IRI) causes tissue and organ injury, in part, through alterations in tissue blood flow and the production of reactive oxygen species. The cell surface receptor signal-regulatory protein-? (SIRP-?) is expressed on inflammatory cells and suppresses phagocytosis, but the function of SIRP-? in IRI has not been determined. We reported previously that the matricellular protein thrombospondin-1 is upregulated in IRI. Here, we report a novel interaction between thrombospondin-1 and SIRP-? on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-?. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-? and downstream activation of Src homology domain 2-containing phosphatase-1. Thrombospondin-1 also stimulated phosphorylation of p47(phox) (an organizer subunit for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1/2) and increased production of superoxide, both of which were abrogated by knockdown or antibody blockade of SIRP-?. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxide-mediated vasodilation in a SIRP-?-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-? signaling axis and was associated with increased superoxide production and cell death. A SIRP-? antibody that blocks thrombospondin-1 activation of SIRP-? mitigated the effects of renal IRI, increasing blood flow, suppressing production of reactive oxygen species, and preserving cellular architecture. A role for CD47 in SIRP-? activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-? on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI.

SUBMITTER: Yao M

PROVIDER: S-EPMC4033366 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Thrombospondin-1 activation of signal-regulatory protein-α stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.

Yao Mingyi M Rogers Natasha M NM Csányi Gábor G Rodriguez Andres I AI Ross Mark A MA St Croix Claudette C Knupp Heather H Novelli Enrico M EM Thomson Angus W AW Pagano Patrick J PJ Isenberg Jeffrey S JS

Journal of the American Society of Nephrology : JASN 20140207 6

Ischemia reperfusion injury (IRI) causes tissue and organ injury, in part, through alterations in tissue blood flow and the production of reactive oxygen species. The cell surface receptor signal-regulatory protein-α (SIRP-α) is expressed on inflammatory cells and suppresses phagocytosis, but the function of SIRP-α in IRI has not been determined. We reported previously that the matricellular protein thrombospondin-1 is upregulated in IRI. Here, we report a novel interaction between thrombospondi ...[more]

PMID: 24511121

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Project description:BackgroundRetinal function is ordered by interactions between transcriptional and posttranscriptional regulators at the molecular level. These regulators include transcription factors (TFs) and posttranscriptional factors such as microRNAs (miRs). Some studies propose that miRs predominantly target the TFs rather than other types of protein coding genes and such studies suggest a possible interconnection of these two regulators in co-regulatory networks.ResultsOur lab has generated mRNA and miRNA microarray expression data to investigate time-dependent changes in gene expression, following induction of ischemia-reperfusion (IR) injury in the rat retina. Data from different reperfusion time points following retinal IR-injury were analyzed. Paired expression data for miRNA-target gene (TG), TF-TG, miRNA-TF were used to identify regulatory loop motifs whose expressions were altered by the IR injury paradigm. These loops were subsequently integrated into larger regulatory networks and biological functions were assayed. Systematic analyses of the networks have provided new insights into retinal gene regulation in the early and late periods of IR. We found both overlapping and unique patterns of molecular expression at the two time points. These patterns can be defined by their characteristic molecular motifs as well as their associated biological processes. We highlighted the regulatory elements of miRs and TFs associated with biological processes in the early and late phases of ischemia-reperfusion injury.ConclusionsThe etiology of retinal ischemia-reperfusion injury is orchestrated by complex and still not well understood gene networks. This work represents the first large network analysis to integrate miRNA and mRNA expression profiles in context of retinal ischemia. It is likely that an appreciation of such regulatory networks will have prognostic potential. In addition, the computational framework described in this study can be used to construct miRNA-TF interactive systems networks for various diseases/disorders of the retina and other tissues.

Dataset Information

Thrombospondin-1 activation of signal-regulatory protein-? stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.

Publications

Thrombospondin-1 activation of signal-regulatory protein-α stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.

Similar Datasets

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