Activation of Parenchymal CD47 Promotes Renal Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion injury (IRI) contributes to decreased allograft function and allograft rejection in transplanted kidneys. Thrombospondin-1 is a stress protein typically secreted in response to hypoxia and the ligand activator for the ubiquitously expressed receptor CD47. The function of activated CD47 in IRI remains completely unknown. Here, we found that both CD47 and its ligand thrombospondin-1 were upregulated after renal IRI in mice. CD47-knockout mice were protected against renal dysfunction and tubular damage, suggesting that the development of IRI requires intact CD47 signaling. Chimeric CD47-knockout mice engrafted with wild-type hematopoietic cells had significantly lower serum creatinine and less tubular damage than wild-type controls after IRI, suggesting that CD47 signaling in parenchymal cells predominantly mediates renal damage. Treatment with a CD47-blocking antibody protected mice from renal dysfunction and tubular damage compared with an isotype control. Taken together, these data imply that CD47 on parenchymal cells promotes injury after renal ischemia and reperfusion. Therefore, CD47 blockade may have therapeutic potential to prevent or suppress ischemia-reperfusion-mediated damage.

Thrombospondin-1 Activation of Signal-Regulatory Protein-α Stimulates Reactive Oxygen Species Production and Promotes Renal Ischemia Reperfusion Injury

“…3,15 To determine whether TSP1 is capable of stimulating O 2 z2 production in VSMC via activation of SIRP-a, we used a specific small interfering RNA (siRNA) (oligo 3) to suppress SIRP-a, then treated cells with TSP1 (2.2 nmol/L for 60 minutes) Figure 2. TSP1-stimulated phosphorylation of VSMC SIRP-a may not depend completely on CD47 activation.…”

“…3 To determine whether TSP1-SIRP-a-mediated stimulation of O 2 z2 is a general finding and extends to other parenchymal cells, we treated human rTECs with TSP1. Human rTECs expressed SIRP-a and SHP1 ( Figure 6, A and B), and TSP1 (2.2 nmol/L) treatment promoted rapid phosphorylation of SIRP-a and SHP1 ( Figure 6C) concurrent with stimulating increased O 2 z2 production ( Figure 6D).…”

“…Here, too, TSP1 treatment increased p-SIRP-a expression in human rTECs ( Figure 6E). Having previously reported rTEC express CD47, 3 we tested whether CD47 is required for TSP1-mediated SIRP-a phosphorylation in rTECs. Wild-type (CD47 +/+ ) and null (CD47 2/2 ) rTECs obtained from kidneys of the respective strains of mice were pre-treated with a SIRP-a antagonist Ab (1 mg/ml) for 15 minutes followed by exogenous TSP1 (2.2 nmol/L) for 60 minutes.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…For example, multiple studies have reported TSP1 induction under hypoxia (11,123,185,187) and in response to ischemia (52,219,241,260) or ischemia-reperfusion injuries (89,125,138,215,217,228,271), situations well known to upregulate ROS. This raises the intriguing hypothesis that ROS signaling may increase TSP1 expression.…”

Rôle de la thrombospondine-1 dans le développement des maladies rénales

“…Après ischémie-reperfusion [27], réduction néphronique [28], obstruction urétérale unilatérale [29], mais aussi au cours du vieillissement rénal [30], du diabète [31] et de nombreuses autres néphropathies glomérulaires expérimentales [32,33], les cellules épithéliales tubulaires expriment de novo la TSP-1. In vitro, l'hypoxie [34] et l'enrichissement du milieu de culture en glucose [31,35] [33]. Chez le rat, l'obstruction urétérale unilatérale induit une expression de novo de l'ARNm de tsp-1 et de la protéine TSP-1 par les tubules lésés.…”