Background The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial
vascular calcification, a process promoted by
hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum
zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear.Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (kl/kl), subtotal
nephrectomy, and
cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD.Results In cultured VSMCs, treatment with
zinc sulfate (ZnSO4) blunted
phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation. ZnSO4 increased the abundance of zinc-finger
protein TNF-α-induced
protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-κB pathway, by
zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO4 under high
phosphate conditions. kl/kl mice showed reduced plasma
zinc levels, and ZnSO4 supplementation strongly blunted
vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO4 ameliorated
vascular calcification in mice with
chronic renal failure and mice with
cholecalciferol overload. In patients with CKD, serum
zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO4 ameliorated the osteoinductive effects of uremic serum in VSMCs.Conclusions
Zinc supplementation ameliorates
phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and
vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF-κB pathway.
Zinc supplementation may be a simple treatment to reduce the burden of
vascular calcification in CKD.