Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB

Jakob Voelkl, Rashad Tuffaha, Trang T.D. Luong, Daniel Zickler, Jaber Masyout, Martina Feger, Nicolas Verheyen, Florian Blaschke, Makoto Kuro-o, Andreas Tomaschitz, Stefan Pilz, Andreas Pasch, Kai Uwe Eckardt, Juergen E. Scherberich, Florian Lang, Burkert Pieske, Ioana Alesutan

Research output: Contribution to journalReview article

17 Citations (Scopus)

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-kB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-a–induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-kB 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-de-pendent induction of TNFAIP3 and subsequent suppression of the NF-kB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.

Original languageEnglish (US)
Pages (from-to)1636-1648
Number of pages13
JournalJournal of the American Society of Nephrology
Volume29
Issue number6
DOIs
StatePublished - Jun 1 2018

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Vascular Calcification
NF-kappa B
Vascular Smooth Muscle
Smooth Muscle Myocytes
Zinc
Serum
Cholecalciferol
Phosphates
Hyperphosphatemia
Zinc Sulfate
Zinc Fingers
Nephrectomy
Chronic Kidney Failure
zinc phosphate
Up-Regulation
Morbidity
Gene Expression
Mortality
Therapeutics
Proteins

ASJC Scopus subject areas

  • Nephrology

Cite this

Voelkl, J., Tuffaha, R., Luong, T. T. D., Zickler, D., Masyout, J., Feger, M., ... Alesutan, I. (2018). Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB. Journal of the American Society of Nephrology, 29(6), 1636-1648. https://doi.org/10.1681/ASN.2017050492

Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB. / 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.

In: Journal of the American Society of Nephrology, Vol. 29, No. 6, 01.06.2018, p. 1636-1648.

Research output: Contribution to journalReview article

Voelkl, J, Tuffaha, R, Luong, TTD, Zickler, D, Masyout, J, Feger, M, Verheyen, N, Blaschke, F, Kuro-o, M, Tomaschitz, A, Pilz, S, Pasch, A, Eckardt, KU, Scherberich, JE, Lang, F, Pieske, B & Alesutan, I 2018, 'Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB', Journal of the American Society of Nephrology, vol. 29, no. 6, pp. 1636-1648. https://doi.org/10.1681/ASN.2017050492
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. / Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 6. pp. 1636-1648.
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title = "Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB",
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-kB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-a–induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-kB 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-de-pendent induction of TNFAIP3 and subsequent suppression of the NF-kB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.",
author = "Jakob Voelkl and Rashad Tuffaha and Luong, {Trang T.D.} and Daniel Zickler and Jaber Masyout and Martina Feger and Nicolas Verheyen and Florian Blaschke and Makoto Kuro-o and Andreas Tomaschitz and Stefan Pilz and Andreas Pasch and Eckardt, {Kai Uwe} and Scherberich, {Juergen E.} and Florian Lang and Burkert Pieske and Ioana Alesutan",
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T1 - Zinc inhibits phosphate-induced vascular calcification through TNFAIP3-mediated suppression of NF-kB

AU - Voelkl, Jakob

AU - Tuffaha, Rashad

AU - Luong, Trang T.D.

AU - Zickler, Daniel

AU - Masyout, Jaber

AU - Feger, Martina

AU - Verheyen, Nicolas

AU - Blaschke, Florian

AU - Kuro-o, Makoto

AU - Tomaschitz, Andreas

AU - Pilz, Stefan

AU - Pasch, Andreas

AU - Eckardt, Kai Uwe

AU - Scherberich, Juergen E.

AU - Lang, Florian

AU - Pieske, Burkert

AU - Alesutan, Ioana

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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-kB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-a–induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-kB 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-de-pendent induction of TNFAIP3 and subsequent suppression of the NF-kB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.

AB - 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-kB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-a–induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-kB 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-de-pendent induction of TNFAIP3 and subsequent suppression of the NF-kB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.

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