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

Mingyi Yao, Natasha M. Rogers, Gábor Csányi, Andres I. Rodriguez, Mark A. Ross, Claudette St. Croix, Heather Knupp, Enrico M. Novelli, Angus W. Thomson, Patrick J. Pagano, Jeffrey S. Isenberg

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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-a (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 thrombospondin-1 and SIRP-α on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-α. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-α and downstreamactivation of Src homology domain 2-containing phosphatase-1. Thrombospondin-1 also stimulated phosphorylation of p47phox (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-α. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxide-mediated vasodilation in a SIRP-α-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-α signaling axis and was associated with increased superoxide production and cell death. A SIRP-α antibody that blocks thrombospondin-1 activation of SIRP-α 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-α activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-α on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI.

Original languageEnglish (US)
Pages (from-to)1171-1186
Number of pages16
JournalJournal of the American Society of Nephrology
Volume25
Issue number6
DOIs
StatePublished - Jun 1 2014

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Thrombospondin 1
Reperfusion Injury
Reactive Oxygen Species
Kidney
Proteins
Superoxides
NADP
Vasodilation
Oxidoreductases
SH2 Domain-Containing Protein Tyrosine Phosphatases
Phosphorylation
Cytophagocytosis
Antibodies
Cell Surface Receptors
Vascular Smooth Muscle
Smooth Muscle Myocytes

ASJC Scopus subject areas

  • Nephrology

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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; Rogers, Natasha M.; Csányi, Gábor; Rodriguez, Andres I.; Ross, Mark A.; St. Croix, Claudette; Knupp, Heather; Novelli, Enrico M.; Thomson, Angus W.; Pagano, Patrick J.; Isenberg, Jeffrey S.

In: Journal of the American Society of Nephrology, Vol. 25, No. 6, 01.06.2014, p. 1171-1186.

Research output: Contribution to journalArticle

Yao, Mingyi ; Rogers, Natasha M. ; Csányi, Gábor ; Rodriguez, Andres I. ; Ross, Mark A. ; St. Croix, Claudette ; Knupp, Heather ; Novelli, Enrico M. ; Thomson, Angus W. ; Pagano, Patrick J. ; Isenberg, Jeffrey S. / Thrombospondin-1 activation of signal-regulatory protein-α stimulates reactive oxygen species production and promotes renal Ischemia reperfusion injury. In: Journal of the American Society of Nephrology. 2014 ; Vol. 25, No. 6. pp. 1171-1186.
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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-a (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 thrombospondin-1 and SIRP-α on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-α. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-α and downstreamactivation of Src homology domain 2-containing phosphatase-1. Thrombospondin-1 also stimulated phosphorylation of p47phox (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-α. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxide-mediated vasodilation in a SIRP-α-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-α signaling axis and was associated with increased superoxide production and cell death. A SIRP-α antibody that blocks thrombospondin-1 activation of SIRP-α 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-α activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-α on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI.",
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AU - Rodriguez, Andres I.

AU - Ross, Mark A.

AU - St. Croix, Claudette

AU - Knupp, Heather

AU - Novelli, Enrico M.

AU - Thomson, Angus W.

AU - Pagano, Patrick J.

AU - Isenberg, Jeffrey S.

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