Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management

Abstract

Ischemia-reperfusion injury (IRI) remains a significant source of early and delayed renal transplant failure. Therapeutic interventions have yet to resolve this ongoing clinical challenge although the reasons for this remain unclear. The cell surface receptor CD47 is widely expressed on vascular cells and in tissues. It has one known soluble ligand, the stress-released matricellular protein thrombospondin-1 (TSP1). The TSP1-CD47 ligand receptor axis controls a number of important cellular processes, inhibiting survival factors such as nitric oxide, cGMP, cAMP, and VEGF, while activating injurious pathways such as production of reactive oxygen species. A role of CD47 in renal IRI was recently revealed by the finding that the TSP1-CD47 axis is induced in renal tubular epithelial cells (RTEC) under hypoxia and following IRI. The absence of CD47 in knockout mice increases survival, mitigates RTEC damage, and prevents subsequent kidney failure. Conversely, therapeutic blockade of TSP1-CD47 signaling provides these same advantages to wild-type animals. Together, these findings suggest an important role for CD47 in renal IRI as a proximate promoter of injury and as a novel therapeutic target.

An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection

“…The dual KD of CD47 and TGFB1 likely works through the perturbation of the interaction of both proteins with the secreted protein, thrombospondin 1 (TSP1). TSP1 is a direct binding partner of CD47 and has been shown to inhibit angiogenesis, modulate extracellular matrix formation and cell migration, suppress to tumor, and most importantly, activate latent TGFB1 [45, 46]. Thus, a reduction in CD47 on the cell surface of cells allows for higher micro environmental levels of TSP1, potentially leading to the activation of more TGFB1, which has been directly shown in murine osteoblasts [44].…”

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

“…CD47 is activated by TSP1 to produce a series of biological effects, including regulation of inflammation, cell adhesion, self-recognition, limitation of cell and animal survival in response to various stressors, and regulation of blood pressure, among other things [11,30,31]. Activation of CD47 by TSP1 inhibits the effects of the NO pathway via limitation of eNOS activity through suppression of calcium flux [32].…”

“…TSP1 engages CD47 via binding to its C-terminal domain and thus limits the downstream effects of the eNOS/NO signaling cascade [11]. Bauer et al reported that both TSP1 and CD47 are significantly upregulated in vascular cells during states of ischemia [12].…”

CD47 does not mediate amyloid-β(1–42) protofibril-stimulated microglial cytokine release

“…CD47, along with ligands thrombospondin-1 (TSP-1) and SIRPα, is involved in numerous physiological and pathological processes including cell spreading, platelet activation, chemotaxis, adhesion, extracellular matrix organization, signaling, survival, proliferation, apoptosis, migration and ischemia-reperfusion injury (reviewed in [26–28]). A potential role for CD47 in AD has also been identified with studies reporting CD47 participation in the microglial proinflammatory response to, and uptake of, fibrillar Aβ [29–31].…”