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

Autor: Andreas Pasch, Burkert Pieske, Daniel Zickler, Ioana Alesutan, Nicolas Verheyen, Juergen E. Scherberich, Jakob Voelkl, Jaber Masyout, Martina Feger, Florian Blaschke, Rashad Tuffaha, Stefan Pilz, Kai-Uwe Eckardt, Andreas Tomaschitz, Makoto Kuro-o, Florian Lang, Trang T.D. Luong
Rok vydání: 2018
Předmět:
0301 basic medicine
Vascular smooth muscle
Gene Expression
Nephrectomy
TNFAIP3
Muscle
Smooth
Vascular
Mice
chemistry.chemical_compound
Hyperphosphatemia
Medicine
Receptor
Aorta
Cells
Cultured
Glucuronidase
Transdifferentiation
NF-kappa B
General Medicine
Nephrocalcinosis
Zinc
Nephrology
Signal Transduction
medicine.medical_specialty
Myocytes
Smooth Muscle
Phosphates
03 medical and health sciences
Downregulation and upregulation
Internal medicine
Animals
Humans
Gene Silencing
Vascular Calcification
Klotho Proteins
Tumor Necrosis Factor alpha-Induced Protein 3
Adaptor Proteins
Signal Transducing
business.industry
medicine.disease
Zinc Sulfate
Disease Models
Animal
Hydroxyethylrutoside
Basic Research
030104 developmental biology
Endocrinology
chemistry
Cell Transdifferentiation
Dietary Supplements
Kidney Failure
Chronic
business
Cholecalciferol
Calcification
Zdroj: Journal of the American Society of Nephrology. 29:1636-1648
ISSN: 1533-3450
1046-6673
DOI: 10.1681/asn.2017050492
Popis: 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 (ZnSO(4)) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation. ZnSO(4) 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 ZnSO(4) under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO(4) supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO(4) 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(4) 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.
Databáze: OpenAIRE
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