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Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia.

ABSTRACT: Thrombospondin 1 (TSP-1) is a matricellular protein that inhibits angiogenesis and causes apoptosis in vivo and in vitro in several cancerous cells and tissues. Here we identify TSP-1 as the molecule with the highest induction level at 3 hours of IR injury in rat and mouse kidneys subjected to ischemia/reperfusion (IR) injury using the DNA microarray approach. Northern hybridizations demonstrated that TSP-1 expression was undetectable at baseline, induced at 3 and 12 hours, and returned to baseline levels at 48 hours of reperfusion. Immunocytochemical staining identified the injured proximal tubules as the predominant sites of expression of TSP-1 in IR injury and showed colocalization of TSP-1 with activated caspase-3. Addition of purified TSP-1 to normal kidney proximal tubule cells or cells subjected to ATP depletion in vitro induced injury as demonstrated by cytochrome c immunocytochemical staining and caspase-3 activity. The deleterious role of TSP-1 in ischemic kidney injury was demonstrated directly in TSP-1 null mice, which showed significant protection against IR injury-induced renal failure and tubular damage. We propose that TSP-1 is a novel regulator of ischemic damage in the kidney and may play an important role in the pathophysiology of ischemic kidney failure.

SUBMITTER: Thakar CV

PROVIDER: S-EPMC1283940 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia.

Thakar Charuhas V CV Zahedi Kamyar K Revelo Monica P MP Wang Zhaohui Z Burnham Charles E CE Barone Sharon S Bevans Shannon S Lentsch Alex B AB Rabb Hamid H Soleimani Manoocher M

The Journal of clinical investigation 20051117 12

Thrombospondin 1 (TSP-1) is a matricellular protein that inhibits angiogenesis and causes apoptosis in vivo and in vitro in several cancerous cells and tissues. Here we identify TSP-1 as the molecule with the highest induction level at 3 hours of IR injury in rat and mouse kidneys subjected to ischemia/reperfusion (IR) injury using the DNA microarray approach. Northern hybridizations demonstrated that TSP-1 expression was undetectable at baseline, induced at 3 and 12 hours, and returned to basel ...[more]

PMID: 16294224

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Project description:Background: Acute kidney injury (AKI) is a severe clinical syndrome, and ischemia-reperfusion injury is an important cause of acute kidney injury. The aim of the present study was to investigate the related genes and pathways in the mouse model of acute kidney injury induced by ischemia-reperfusion injury (IRI-AKI). Method: Two public datasets (GSE39548 and GSE131288) originating from the NCBI Gene Expression Omnibus (GEO) database were analyzed using the R software limma package, and differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) and gene set enrichment analysis (GSEA) were performed using the differentially expressed genes. Furthermore, a protein-protein interaction (PPI) network was constructed to investigate hub genes, and transcription factor (TF)-hub gene and miRNA-hub gene networks were constructed. Drugs and molecular compounds that could interact with hub genes were predicted using the DGIdb. Result: A total of 323 common differentially expressed genes were identified in the renal ischemia-reperfusion injury group compared with the control group. Among these, 260 differentially expressed genes were upregulated and 66 differentially expressed genes were downregulated. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes analysis results showed that these common differentially expressed genes were enriched in positive regulation of cytokine production, muscle tissue development, and other biological processes, indicating that they were involved in mitogen-activated protein kinase (MAPK), PI3K-Akt, TNF, apoptosis, and Epstein-Barr virus infection signaling pathways. Protein-protein interaction analysis showed 10 hub genes, namely, Jun, Stat3, MYC, Cdkn1a, Hif1a, FOS, Atf3, Mdm2, Egr1, and Ddit3. Using the STRUST database, starBase database, and DGIdb database, it was predicted that 34 transcription factors, 161 mi-RNAs, and 299 drugs or molecular compounds might interact with hub genes. Conclusion: Our findings may provide novel potential biomarkers and insights into the pathogenesis of ischemia-reperfusion injury-acute kidney injury through a comprehensive analysis of Gene Expression Omnibus data, which may provide a reliable basis for early diagnosis and treatment of ischemia-reperfusion injury-acute kidney injury.

Dataset Information

Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia.

Publications

Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia.

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