CD47 Blockade Reduces Ischemia-Reperfusion Injury and Improves Outcomes in a Rat Kidney Transplant Model

Lin, Yiing; Manning, Pamela T.; Jia, Jianluo; Gaut, Joseph P.; Xiao, Zhenyu; Capoccia, Benjamin J.; Chen, Chuncheng; Hiebsch, Ronald R.; Upadhya, Gundumi A.; Mohanakumar, Thalachallour; Frazier, William A.; Chapman, William C.

doi:10.1097/tp.0000000000000252

Cited by 29 publications

(35 citation statements)

References 22 publications

(27 reference statements)

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“…In liver and kidney I/R models, CD47 knockout mice were found to suffer less damage compared to control mice after periods of vascular occlusion followed by recanalization [13,17]. Administration of the CD47 monoclonal antibody similarly improved the survival of ischemic skin flaps and skin grafts, and both liver and kidney mouse I/R models [14,15,38,39].…”

Section: Down-regulation Of Cd47 Attenuates I/r Induced Oxidative Strmentioning

confidence: 89%

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

Wang

Yang²,

Ding³

et al. 2016

Cell Physiol Biochem

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Key Words CD47 • Ischemia/reperfusion injury • Endothelial nitric oxide synthase • Oxidative stress • RNA interferenceAbstract Background/Aims: Oxidative stress is strongly implicated in the pathogenesis of myocardial damage caused by ischemia reperfusion (I/R). Previous studies have confirmed that cardiac CD47 drives left ventricular heart failure. However, the role for CD47 in myocardial I/R injury (MIRI) has not previously been proposed. This study was designed to investigate whether down-regulation of CD47 using RNA interference (RNAi) technology can relieve inhibition of nitric oxide signaling and attenuate myocardial damage in a rat model of I/R. Methods: Male Sprague-Dawley rats (n = 40) were randomly allocated to four groups and pre-treated either with saline (Sham and I/R groups), or adenovirus expressing either control (Ad-EGFP-N) or CD47-targeting (Ad-EGFP-CD47) RNAi. After four days, the rat MIRI model was established by occluding the left anterior descending coronary artery for 30 min, followed by reperfusion for 3 h. Heart tissue was harvested and assessed by immunohistochemistry, western blot, and quantitative RT-PCR. Outcome measures included infarct size, myocardial enzyme (creatine kinase, creatine kinase-MB, and lactate dehydrogenase) levels in serum, markers of oxidative stress, and morphological changes to the myocardium. Results: Delivery of Ad-EGFP-CD47 RNAi into the myocardium remarkably decreased CD47 expression levels. Down-regulation of CD47 was significantly associated with reduced infarct size and serum levels of myocardial enzymes, increased activity of endothelial nitric oxide synthase, increased levels of nitric oxide, and decreased levels of oxidative stress. Conclusion: These data indicate that down-regulation H.-b. Wang and J. Yang contributed equally to this work.

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Section: Down-regulation Of Cd47 Attenuates I/r Induced Oxidative Strmentioning

confidence: 89%

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

Wang

Yang²,

Ding³

et al. 2016

Cell Physiol Biochem

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“…Animal studies further suggest that targeting CD47 could improve healing in diet-induced vasculopathy and ameliorate the effects of cardiac hypertrophy (Isenberg et al, 2007a, Sharifi-Sanjani et al, 2014). The protective activities of antibodies targeting CD47 in liver and kidney ischemia-reperfusion injury models suggest applications in organ transplantation (Isenberg et al, 2008b, Rogers et al, 2012, Lin et al, 2014). Antibodies targeting CD47 to block SIRPα signaling are entering clinical testing to enhance macrophage-mediated clearance of cancers, but the same humanized antibody may also block TSP1-induced signaling through CD47.…”

Section: Discussionmentioning

confidence: 99%

CD47 signaling pathways controlling cellular differentiation and responses to stress

Soto-Pantoja

Kaur

Roberts

2015

Critical Reviews in Biochemistry and Molecular Biology

153

166

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CD47 is a widely expressed integral membrane protein that serves as the counter-receptor for the inhibitory phagocyte receptor signal-regulatory protein-α (SIRPα) and as a signaling receptor for the secreted matricellular protein thrombospondin-1. Recent studies employing mice and somatic cells lacking CD47 have revealed important pathophysiological functions of CD47 in cardiovascular homeostasis, immune regulation, resistance of cells and tissues to stress, and chronic diseases of aging including cancer. With the emergence of experimental therapeutics targeting CD47, a more thorough understanding of CD47 signal transduction is essential. CD47 lacks a substantial cytoplasmic signaling domain, but several cytoplasmic binding partners have been identified, and lateral interactions of CD47 with other membrane receptors play important roles in mediating signaling resulting from the binding of thrombospondin-1. This review addresses recent advances in identifying the lateral binding partners, signal transduction pathways, and downstream transcription networks regulated through CD47 in specific cell lineages. Major pathways regulated by CD47 signaling include calcium homeostasis, cyclic nucleotide signaling, nitric oxide and hydrogen sulfide biosynthesis and signaling, and stem cell transcription factors. These pathways and other undefined proximal mediators of CD47 signaling regulate cell death and protective autophagy responses, mitochondrial biogenesis, cell adhesion and motility, and stem cell self-renewal. Although thrombospondin-1 is the best characterized agonist of CD47, the potential roles of other members of the thrombospondin family, SIRPα and SIRPγ binding, and homotypic CD47 interactions as agonists or antagonists of signaling through CD47 should also be considered.

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“…45 The beneficial effect of TSP1-CD47 blockade in reducing renal and liver IRI has been demonstrated in rat models. 25,46 We provide additional mechanistic insight into a mouse syngeneic renal transplant model. Antibody blockade of CD47 mitigated proinflammatory cytokine production, upregulated multiple self-renewal transcription factors, and improved renal function.…”

Section: Tsp1-induced Cd47 Receptor Activationmentioning

confidence: 99%

CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion

Rogers

Zhang

Wang

et al. 2016

Kidney International

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Defects in renal tubular epithelial cell repair contribute to renal ischemia reperfusion injury, cause acute kidney damage, and promote chronic renal disease. The matricellular protein thrombospondin-1 and its receptor CD47 are involved in experimental renal ischemia reperfusion injury, although the role of this interaction in renal recovery is unknown. We found upregulation of self-renewal genes (transcription factors Oct4, Sox2, Klf4 and cMyc) in the kidney of CD47(-/-) mice after ischemia reperfusion injury. Wild-type animals had minimal self-renewal gene expression, both before and after injury. Suggestive of cell autonomy, CD47(-/-) renal tubular epithelial cells were found to increase expression of the self-renewal genes. This correlated with enhanced proliferative capacity compared with cells from wild-type mice. Exogenous thrombospondin-1 inhibited self-renewal gene expression in renal tubular epithelial cells from wild-type but not CD47(-/-) mice, and this was associated with decreased proliferation. Treatment of renal tubular epithelial cells with a CD47 blocking antibody or CD47-targeting small interfering RNA increased expression of some self-renewal transcription factors and promoted cell proliferation. In a syngeneic kidney transplant model, treatment with a CD47 blocking antibody increased self-renewal transcription factor expression, decreased tissue damage, and improved renal function compared with that in control mice. Thus, thrombospondin-1 via CD47 inhibits renal tubular epithelial cell recovery after ischemia reperfusion injury through inhibition of proliferation/self-renewal.

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CD47 Blockade Reduces Ischemia-Reperfusion Injury and Improves Outcomes in a Rat Kidney Transplant Model

Cited by 29 publications

References 22 publications

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

CD47 signaling pathways controlling cellular differentiation and responses to stress

CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion

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