Arterial “inflammaging” drives vascular calcification in children on dialysis

Pilar Sanchis; Chin Yee Ho; Yiwen Liu; Leilani E. Beltran; Sadia Ahmad; Anne P. Jacob; Malgorzata Furmanik; Joanne Laycock; David A. Long; Rukshana Shroff; Catherine M. Shanahan

doi:10.1016/j.kint.2018.12.014

Arterial “inflammaging” drives vascular calcification in children on dialysis

Pilar Sanchis, Chin Yee Ho, Yiwen Liu, Leilani E. Beltran, Sadia Ahmad, Anne P. Jacob, Malgorzata Furmanik, Joanne Laycock, David A. Long, Rukshana Shroff, Catherine M. Shanahan^*

^*Corresponding author for this work

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Abstract

Children on dialysis have a cardiovascular mortality risk equivalent to older adults in the general population, with the development of medial vascular calcification, an age-associated pathology. We hypothesized that premature vascular ageing contributes to calcification in children with advanced chronic kidney disease (CKD). Vessels from children with Stage 5 CKD with and without dialysis had evidence of increased oxidative DNA damage. The senescence markers p16 and p21 were also increased in vessels from children on dialysis. Treatment of vessel rings ex vivo with calcifying media increased oxidative DNA damage in vessels from children with Stage 5 CKD, but not in those from healthy controls. Vascular smooth muscle cells cultured from children on dialysis exhibited persistent DNA damage, impaired DNA damage repair, and accelerated senescence. Under calcifying conditions vascular smooth muscle cells from children on dialysis showed increased osteogenic differentiation and calcification. These changes correlated with activation of the senescence-associated secretory phenotype (SASP), an inflammatory phenotype characterized by the secretion of proinflammatory cytokines and growth factors. Blockade of ATM-mediated DNA damage signaling reduced both inflammation and calcification. Clinically, children on dialysis had elevated circulating levels of osteogenic SASP factors that correlated with increased vascular stiffness and coronary artery calcification. These data imply that dysregulated mineral metabolism drives vascular ‘inflammaging’ by promoting oxidative DNA damage, premature senescence, and activation of a pro-inflammatory SASP. Drugs that target DNA damage signaling or eliminate senescent cells may have the potential to prevent vascular calcification in patients with advanced CKD.

Original language	English
Pages (from-to)	958-972
Number of pages	15
Journal	Kidney International
Volume	95
Issue number	4
Early online date	1 Mar 2019
DOIs	https://doi.org/10.1016/j.kint.2018.12.014
Publication status	Published - 1 Apr 2019

Keywords

aging
calcification
dialysis
senescence
vascular smooth muscle cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Arterial “inflammaging” drives vascular_SANCHIS_Accepted6December2018_GOLD AAM (CC BY)Accepted author manuscript, 2.81 MBLicence: CC BY
Arterial “inflammaging” drives vascular_SANCHIS_Accepted6December2018_GOLD VoR (CC BY)Final published version, 3.75 MBLicence: CC BY

Cite this

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title = "Arterial “inflammaging” drives vascular calcification in children on dialysis",

abstract = "Children on dialysis have a cardiovascular mortality risk equivalent to older adults in the general population, with the development of medial vascular calcification, an age-associated pathology. We hypothesized that premature vascular ageing contributes to calcification in children with advanced chronic kidney disease (CKD). Vessels from children with Stage 5 CKD with and without dialysis had evidence of increased oxidative DNA damage. The senescence markers p16 and p21 were also increased in vessels from children on dialysis. Treatment of vessel rings ex vivo with calcifying media increased oxidative DNA damage in vessels from children with Stage 5 CKD, but not in those from healthy controls. Vascular smooth muscle cells cultured from children on dialysis exhibited persistent DNA damage, impaired DNA damage repair, and accelerated senescence. Under calcifying conditions vascular smooth muscle cells from children on dialysis showed increased osteogenic differentiation and calcification. These changes correlated with activation of the senescence-associated secretory phenotype (SASP), an inflammatory phenotype characterized by the secretion of proinflammatory cytokines and growth factors. Blockade of ATM-mediated DNA damage signaling reduced both inflammation and calcification. Clinically, children on dialysis had elevated circulating levels of osteogenic SASP factors that correlated with increased vascular stiffness and coronary artery calcification. These data imply that dysregulated mineral metabolism drives vascular {\textquoteleft}inflammaging{\textquoteright} by promoting oxidative DNA damage, premature senescence, and activation of a pro-inflammatory SASP. Drugs that target DNA damage signaling or eliminate senescent cells may have the potential to prevent vascular calcification in patients with advanced CKD.",

keywords = "aging, calcification, dialysis, senescence, vascular smooth muscle cells",

author = "Pilar Sanchis and Ho, {Chin Yee} and Yiwen Liu and Beltran, {Leilani E.} and Sadia Ahmad and Jacob, {Anne P.} and Malgorzata Furmanik and Joanne Laycock and Long, {David A.} and Rukshana Shroff and Shanahan, {Catherine M.}",

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doi = "10.1016/j.kint.2018.12.014",

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T1 - Arterial “inflammaging” drives vascular calcification in children on dialysis

AU - Sanchis, Pilar

AU - Ho, Chin Yee

AU - Liu, Yiwen

AU - Beltran, Leilani E.

AU - Ahmad, Sadia

AU - Jacob, Anne P.

AU - Furmanik, Malgorzata

AU - Laycock, Joanne

AU - Long, David A.

AU - Shroff, Rukshana

AU - Shanahan, Catherine M.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Children on dialysis have a cardiovascular mortality risk equivalent to older adults in the general population, with the development of medial vascular calcification, an age-associated pathology. We hypothesized that premature vascular ageing contributes to calcification in children with advanced chronic kidney disease (CKD). Vessels from children with Stage 5 CKD with and without dialysis had evidence of increased oxidative DNA damage. The senescence markers p16 and p21 were also increased in vessels from children on dialysis. Treatment of vessel rings ex vivo with calcifying media increased oxidative DNA damage in vessels from children with Stage 5 CKD, but not in those from healthy controls. Vascular smooth muscle cells cultured from children on dialysis exhibited persistent DNA damage, impaired DNA damage repair, and accelerated senescence. Under calcifying conditions vascular smooth muscle cells from children on dialysis showed increased osteogenic differentiation and calcification. These changes correlated with activation of the senescence-associated secretory phenotype (SASP), an inflammatory phenotype characterized by the secretion of proinflammatory cytokines and growth factors. Blockade of ATM-mediated DNA damage signaling reduced both inflammation and calcification. Clinically, children on dialysis had elevated circulating levels of osteogenic SASP factors that correlated with increased vascular stiffness and coronary artery calcification. These data imply that dysregulated mineral metabolism drives vascular ‘inflammaging’ by promoting oxidative DNA damage, premature senescence, and activation of a pro-inflammatory SASP. Drugs that target DNA damage signaling or eliminate senescent cells may have the potential to prevent vascular calcification in patients with advanced CKD.

AB - Children on dialysis have a cardiovascular mortality risk equivalent to older adults in the general population, with the development of medial vascular calcification, an age-associated pathology. We hypothesized that premature vascular ageing contributes to calcification in children with advanced chronic kidney disease (CKD). Vessels from children with Stage 5 CKD with and without dialysis had evidence of increased oxidative DNA damage. The senescence markers p16 and p21 were also increased in vessels from children on dialysis. Treatment of vessel rings ex vivo with calcifying media increased oxidative DNA damage in vessels from children with Stage 5 CKD, but not in those from healthy controls. Vascular smooth muscle cells cultured from children on dialysis exhibited persistent DNA damage, impaired DNA damage repair, and accelerated senescence. Under calcifying conditions vascular smooth muscle cells from children on dialysis showed increased osteogenic differentiation and calcification. These changes correlated with activation of the senescence-associated secretory phenotype (SASP), an inflammatory phenotype characterized by the secretion of proinflammatory cytokines and growth factors. Blockade of ATM-mediated DNA damage signaling reduced both inflammation and calcification. Clinically, children on dialysis had elevated circulating levels of osteogenic SASP factors that correlated with increased vascular stiffness and coronary artery calcification. These data imply that dysregulated mineral metabolism drives vascular ‘inflammaging’ by promoting oxidative DNA damage, premature senescence, and activation of a pro-inflammatory SASP. Drugs that target DNA damage signaling or eliminate senescent cells may have the potential to prevent vascular calcification in patients with advanced CKD.

KW - aging

KW - calcification

KW - dialysis

KW - senescence

KW - vascular smooth muscle cells

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JO - Kidney International

JF - Kidney International

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ER -

Arterial “inflammaging” drives vascular calcification in children on dialysis

Abstract

Keywords

UN SDGs

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