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International urology and nephrology
Oct, 2022;54 (10): 2719-2731.

Both high glucose and phosphate overload promote senescence-associated calcification of vascular muscle cells.

Mingming Zhang, Tianyu Li, Zhenzhen Tu, Yuying Zhang, Xuerong Wang, Dandan Zang, Deping Xu, Yang Feng, Fan He, Mingyue Ni, Deguang Wang, Haisheng Zhou
Author Information
  1. Mingming Zhang: Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China. ORCID
  2. Tianyu Li: Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  3. Zhenzhen Tu: Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China.
  4. Yuying Zhang: Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  5. Xuerong Wang: Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  6. Dandan Zang: The Center for Scientific Research of Anhui Medical University, Hefei, China.
  7. Deping Xu: Department of Clinical Laboratory, Affiliated Hefei Hospital of Anhui Medical University, Hefei, China.
  8. Yang Feng: Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China.
  9. Fan He: Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China.
  10. Mingyue Ni: Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China.
  11. Deguang Wang: Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China. wangdeguang@ahmu.edu.cn.
  12. Haisheng Zhou: Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, China.
PMID: 35396645 DOI: 10.1007/s11255-022-03195-4

Abstract

PURPOSE: The NAD-dependent deacetylase, sirtuin 1 (SIRT1), plays an important role in vascular calcification induced by high glucose and/or high phosphate levels. However, the mechanism by which SIRT1 regulates this process is still not fully understood. Thus, this study aimed to determine the role of high glucose and phosphate in vascular calcification and the molecular mechanisms underlying SIRT1 regulation.
METHODS: Vascular smooth muscle cells (VSMCs) were cultured under normal, high phosphate, and/or high-glucose conditions for 9 days. Alizarin red staining and calcification content analyses were used to determine calcium deposition. VSMC senescence was detected by β-galactosidase (SA-β-Gal) staining and p21 expression.
RESULTS: Mouse VSMCs exposed to high phosphate and high glucose in vitro showed increased calcification, which was correlated with the induction of cell senescence, as confirmed by the increased SA-β-galactosidase activity and p21 expression. SRT1720, an activator of SIRT1, inhibits p65 acetylation, the nuclear factor-κ-gene binding (NF-κB) pathway, and VSMC transdifferentiation, prevents senescence and reactive oxygen species (ROS) production, and reduces vascular calcification. In contrast, sirtinol, an inhibitor of SIRT1, increases p65 acetylation, activates the NF-κB pathway, induces vascular smooth muscle cell transdifferentiation and senescence, and promotes vascular calcification.
CONCLUSIONS: High glucose and high phosphate levels induce senescence and vascular calcification in VSMCs, and the combined effect of high glucose and phosphate can inhibit SIRT1 expression. SIRT1 inhibits vascular smooth muscle cell senescence and osteogenic differentiation by inhibiting NF-κB activity, thereby inhibiting vascular calcification.

Keywords

High glucose High phosphate SIRT1 Senescence Vascular calcification

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Grants

  1. 2008085MH244/natural science foundation of anhui province

MeSH Term

Animals
Cells, Cultured
Glucose
Mice
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
NF-kappa B
Osteogenesis
Phosphates
Sirtuin 1
Vascular Calcification
beta-Galactosidase

Chemicals

NF-kappa B
Phosphates
beta-Galactosidase
Sirtuin 1
Glucose
Journal Article

Word Cloud

Created with Highcharts 10.0.0calcificationvascularhighSIRT1phosphateglucosesenescencemusclesmoothVSMCsexpressioncellNF-κBHighroleand/orlevelsdetermineVascularcellsstainingVSMCp21increasedactivityinhibitsp65acetylationpathwaytransdifferentiationinhibitingPURPOSE:NAD-dependentdeacetylasesirtuin1playsimportantinducedHowevermechanismregulatesprocessstillfullyunderstoodThusstudyaimedmolecularmechanismsunderlyingregulationMETHODS:culturednormalhigh-glucoseconditions9 daysAlizarinredcontentanalysesusedcalciumdepositiondetectedβ-galactosidaseSA-β-GalRESULTS:MouseexposedvitroshowedcorrelatedinductionconfirmedSA-β-galactosidaseSRT1720activatornuclearfactor-κ-genebindingpreventsreactiveoxygenspeciesROSproductionreducescontrastsirtinolinhibitorincreasesactivatesinducespromotesCONCLUSIONS:inducecombinedeffectcaninhibitosteogenicdifferentiationtherebyoverloadpromotesenescence-associatedSenescence

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