Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF- κ B

• Published in: Journal of the American Society of Nephrology 2018-06, Vol.29 (6), p.1636-1648
• Main Authors: Voelkl, Jakob, Tuffaha, Rashad, Luong, Trang T D, Zickler, Daniel, Masyout, Jaber, Feger, Martina, Verheyen, Nicolas, Blaschke, Florian, Kuro-O, Makoto, Tomaschitz, Andreas, Pilz, Stefan, Pasch, Andreas, Eckardt, Kai-Uwe, Scherberich, Juergen E, Lang, Florian, Pieske, Burkert, Alesutan, Ioana
• Format: Article
• Language: English
• Subjects: Basic Research
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2017050492

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. We performed experiments in primary human aortic VSMCs; klotho-hypomorphic ( ), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD. In cultured VSMCs, treatment with zinc sulfate (ZnSO ) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF- B activation. ZnSO increased the abundance of zinc-finger protein TNF- -induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF- B pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO under high phosphate conditions. mice showed reduced plasma zinc levels, and ZnSO supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO 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, ZnSO ameliorated the osteoinductive effects of uremic serum in VSMCs. 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- B pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.