CCL7 suppression alleviates vascular injury by blocking the CCR5/STAT1 signaling pathway in chronic kidney disease.

Patients with chronic kidney disease (CKD) are at significantly increased risk of cardiovascular disease. Indoxyl sulfate (IS) is a notorious uremic toxin linked to peripheral arterial disease (PAD), and chemokine CC motif ligand 7 (CCL7) is an inflammatory chemokine. We hypothesized that CCL7 plays an essential role in PAD under CKD conditions. This study aimed to elucidate whether CCL7 inhibition could be a potential therapeutic target for PAD in CKD. The 5/6 nephrectomy-induced CKD and folic acid (FA)-induced CKD were used as mouse models of CKD. To determine the specific role of CCL7, experiments were conducted using CCL7 neutralizing antibodies and the CCL7 gene deletion. Serum CCL7 concentrations were elevated in CKD mice. Blood perfusion in the ischemic limb was reduced, and wound healing was delayed in CKD animals, but the administration of the CCL7 antibody enhanced neovascularization in ischemic limbs and accelerated wound healing by increasing capillary density and upregulating the expression of angiogenic proteins. Additionally, deletion of the CCL7 gene in FA-induced CKD mice promoted angiogenesis in ischemic limbs and wound areas, leading to improved blood flow and tissue repair. In IS-stimulated human aortic endothelial cells, tube formation and migration abilities were inhibited, and treatment with the CCL7 antibody or CCL7 siRNA repaired cell dysfunction and upregulated angiogenic factors by downregulating the CC motif chemokine receptor 5/signal transducer and activator of the transcription signaling pathway. In conclusion, this study provides a mechanistic basis for the role of potential CCL7-based therapeutic interventions in vascular complications of CKD.