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

Area of Science:

• Vascular Biology
• Nephrology
• Cellular Biology

Background:

• Chronic kidney disease (CKD) accelerates vascular dysfunction and cardiovascular disease.
• Uremic toxins, like indoxyl sulphate (IS), and Thrombospondin-1 (TSP1) signaling are implicated in vascular pathology.
• The specific role of TSP1-CD47 signaling in CKD-associated vascular remodeling remains unclear.

Purpose of the Study:

• To investigate the contribution of TSP1-CD47 signaling to vascular smooth muscle cell (VSMC) dysfunction in CKD.
• To explore the therapeutic potential of targeting CD47 in CKD.

Main Methods:

• Human aortic VSMCs (hVSMCs) were treated with IS, TSP1, or plasma from CKD patients.
• CKD was induced in wild-type (WT) and CD47-deficient (CD47KO) mice via 5/6 nephrectomy.
• Vascular changes were assessed using histology, immunohistochemistry, and molecular analyses.

Main Results:

• IS, TSP1, and CKD plasma increased TSP1 expression, reduced proliferation, and activated ERK1/2 and aryl hydrocarbon receptor (AhR) in hVSMCs.
• These effects were attenuated by CD47 blockade, and CKD plasma exacerbated IS- and TSP1-induced senescence.
• In vivo, CD47 deletion protected against CKD-induced aortic wall thickening and reduced pERK1/2 levels.

Conclusions:

• IS and TSP1 promote VSMC senescence through CD47-dependent ERK1/2 and AhR signaling.
• CD47 deletion confers protection against CKD-induced vascular remodeling.
• Targeting CD47 may offer a novel therapeutic strategy for mitigating vascular complications in CKD.