Thrombospondin 1–CD47 Signalling Modulates Vascular Smooth Muscle Cell Senescence in Chronic Kidney Disease

TL;DR

This study shows that blocking CD47 may help prevent blood vessel damage in chronic kidney disease by reducing cell aging.

Contribution

The novel finding is that CD47 signaling mediates vascular smooth muscle cell senescence in CKD, suggesting CD47 as a therapeutic target.

Findings

CD47 deletion in mice prevents aortic wall thickening caused by chronic kidney disease.

TSP1 and indoxyl sulphate induce senescence in vascular smooth muscle cells via CD47-dependent pathways.

Blocking CD47 reduces ERK1/2 and AhR activation in cells exposed to CKD plasma.

Abstract

Chronic kidney disease (CKD) accelerates vascular dysfunction and cardiovascular disease, partly through the accumulation of the uraemic toxin indoxyl sulphate (IS). Thrombospondin-1 (TSP1) and its receptor CD47 have been implicated in vascular pathology, but their role in CKD-associated vascular remodelling is unknown. We investigated the contribution of TSP1–CD47 signalling to vascular smooth muscle cell (VSMC) dysfunction in CKD. Human aortic VSMCs (hVSMCs) were exposed to IS, TSP1, or plasma from patients with CKD. CKD was induced in wild-type (WT) and CD47-deficient (CD47KO) mice using 5/6 nephrectomy. Vascular changes were assessed by histology, immunohistochemistry, and molecular analyses. IS, TSP1, and CKD plasma increased TSP1 expression in hVSMCs, reduced proliferation, elevated β-galactosidase activity, and activated phosphorylated ERK1/2 and cytoplasmic aryl hydrocarbon receptor. These effects were attenuated by CD47 blockade. CKD plasma further enhanced IS- and TSP1-induced senescence. In vivo, 5/6 nephrectomy induced aortic wall thickening in WT but not in CD47KO mice. Aortic pERK1/2 was reduced in CD47KO mice despite persistent TSP1 upregulation. IS and TSP1 promote VSMC senescence through CD47-dependent ERK1/2 and AhR signalling. CD47 deletion protects against CKD-induced vascular remodelling, suggesting that CD47 blockade may represent a novel therapeutic strategy to mitigate vascular complications in CKD.

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