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Updated: Feb 11, 2026
Analysis of Extracellular Vesicle-Mediated Vascular Calcification Using In Vitro and In Vivo Models
Published on: January 27, 2023
Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB
Jakob Voelkl1, Rashad Tuffaha2, Trang T D Luong3
1Department of Internal Medicine and Cardiology, Charité- Universitätsmedizin Berlin, Berlin, Germany; jakob.voelkl@charite.de.
Insights
Zinc supplementation can prevent vascular calcification in chronic kidney disease (CKD) by inhibiting osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). This occurs through the GPR39-dependent induction of TNFAIP3, which suppresses the NF-κB pathway, offering a potential treatment for CKD patients.
Area of Science:
- Biochemistry
- Nephrology
- Cardiovascular Biology
Background:
- Patients with chronic kidney disease (CKD) exhibit high cardiovascular morbidity and mortality, largely due to medial vascular calcification.
- Vascular calcification in CKD is promoted by hyperphosphatemia and involves the osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs).
- Reduced serum zinc levels are common in CKD patients, but their functional role in vascular calcification is not well understood.
Purpose of the Study:
- To investigate the functional relevance of zinc in vascular calcification associated with CKD.
- To elucidate the cellular mechanisms by which zinc affects vascular smooth muscle cell transdifferentiation and calcification.
- To evaluate the therapeutic potential of zinc supplementation in mitigating vascular calcification in CKD.
Main Methods:
- Experiments were conducted using primary human aortic VSMCs and various mouse models of vascular calcification (klotho-hypomorphic, subtotal nephrectomy, cholecalciferol overload).
- The study analyzed serum samples from CKD patients to correlate zinc levels with calcification propensity.
- Key pathways investigated included NF-κB activation, TNFAIP3 (A20) expression, and osteo-/chondrogenic signaling in response to zinc treatment.
Main Results:
- Zinc sulfate (ZnSO4) treatment inhibited phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation in cultured VSMCs.
- ZnSO4 increased TNFAIP3 (A20) expression via the zinc-sensing receptor GPR39, suppressing the NF-κB pathway; TNFAIP3 silencing abrogated ZnSO4's anticalcific effect.
- ZnSO4 supplementation reduced vascular calcification and aortic osteoinduction in multiple mouse models and normalized calcification propensity in CKD patients' serum.
Conclusions:
- Zinc supplementation ameliorates VSMC osteo-/chondrogenic transdifferentiation and vascular calcification in a GPR39-dependent manner, mediated by TNFAIP3 induction and NF-κB suppression.
- These findings highlight a novel cellular mechanism underlying zinc's protective effects against vascular calcification.
- Zinc supplementation represents a potential simple therapeutic strategy to reduce the significant burden of vascular calcification in CKD patients.
Abstract:
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.
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