| First Author | Yao M | Year | 2014 |
| Journal | J Am Soc Nephrol | Volume | 25 |
| Issue | 6 | Pages | 1171-86 |
| PubMed ID | 24511121 | Mgi Jnum | J:345760 |
| Mgi Id | MGI:6835071 | Doi | 10.1681/ASN.2013040433 |
| Citation | Yao M, et al. (2014) Thrombospondin-1 activation of signal-regulatory protein-alpha stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury. J Am Soc Nephrol 25(6):1171-86 |
| abstractText | 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-alpha (SIRP-alpha) is expressed on inflammatory cells and suppresses phagocytosis, but the function of SIRP-alpha 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-alpha on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-alpha. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-alpha 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-alpha. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxide-mediated vasodilation in a SIRP-alpha-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-alpha signaling axis and was associated with increased superoxide production and cell death. A SIRP-alpha antibody that blocks thrombospondin-1 activation of SIRP-alpha 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-alpha activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-alpha on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI. |
