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Signal Inhibitory Regulatory Protein-α Regulates Pathologic Reactive Oxygen Species in Acute Kidney Injury.

N. Rogers,1,2,3 D. Meijles,3 P. Pagano,3 J. Isenberg.3

1Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
2Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA
3Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA

Meeting: 2017 American Transplant Congress

Abstract number: 546

Keywords: Epithelial cells, NADPH oxidase, Reactive oxygen species, Renal ischemia

Session Information

Session Name: Concurrent Session: Pathways in Ischemia Reperfusion

Session Type: Concurrent Session

Date: Tuesday, May 2, 2017

Session Time: 4:30pm-6:00pm

 Presentation Time: 4:54pm-5:06pm

Location: E351

Background: Ischemia reperfusion injury (IRI) is mediated by a complex cascade of pro-inflammatory and oxidative processes. We have reported that signal regulatory inhibitory protein (SIRP)-α is expressed by renal tubular epithelial cells (rTEC). We have also shown that the stress-response protein thrombospondin-1 (TSP1) is increased following renal IRI and binds to SIRPα. However, it is unclear how TSP1-SIRPα signaling contributes to the pathophysiology of IRI.

Methods: Age-matched male wild-type (WT) mice, and SIRPα mutant mice (SIRPαmut, lacking the cytoplasmic recruitment domains) underwent bilateral renal IRI and were assessed for renal function and biomolecular analysis. WT and SIRPαmut rTEC were studied in vitro. As SIRPα is expressed by rTEC and non-parenchymal cells, chimeric mice were generated to explore the contribution of differing cell compartments to IRI; mice were irradiated and rescued with WT or SIRPαmut bone marrow.

Results: IRI resulted in significantly elevated serum creatinine in WT mice, which was mitigated in SIRPαmut animals (2.3±0.4 in WT versus 0.98±0.4 mg/dl in SIRPαmut, p<0.01). Changes in renal function reflected improvements in SIRPαmut histologic findings, inflammatory infiltrate (Ly6G+neutrophils and F4/80+macrophages) and levels of pro-inflammatory cytokines (IL-1ß, TNFα, IL-6). TSP1 was expressed to a similar degree post-IRI regardless of genetic background. Measurement of reactive oxygen species (ROS) by cytochrome c assay in whole kidney demonstrated a 2-fold increase in superoxide anion in WT mice post-IRI (p<0.001) but not in SIRPαmut mice, compared to sham-operated controls. Expression of oxidative protein modification 3-nitrotyrosine was reduced in SIRPαmut mice compared to WT, although total renal expression of NADPH oxidase 1, 2 and 4 were unchanged. WT rTEC displayed 3-fold upregulated ROS in response to exogenous TSP1 (p<0.01), which did not occur in SIRPαmut cells. SIRPαmut mice, regardless of hematopoietic reconstitution, were fully protected against renal dysfunction and ROS generation following IRI.

Conclusion: These data provide evidence for a role for SIRPα promoting renal IRI through generation of pathologic ROS, and blockade of SIRPα may provide a novel therapeutic target to modify IR-mediated damage.

CITATION INFORMATION: Rogers N, Meijles D, Pagano P, Isenberg J. Signal Inhibitory Regulatory Protein-α Regulates Pathologic Reactive Oxygen Species in Acute Kidney Injury. Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Rogers N, Meijles D, Pagano P, Isenberg J. Signal Inhibitory Regulatory Protein-α Regulates Pathologic Reactive Oxygen Species in Acute Kidney Injury. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/signal-inhibitory-regulatory-protein-regulates-pathologic-reactive-oxygen-species-in-acute-kidney-injury/. Accessed June 17, 2025.

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