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00925njm 22002777a 4500 dc Sanchis, Pilar author Ho, Chin Yee author Liu, Yiwen author Beltran, Leilani E author Ahmad, Sadia author Jacob, Anne P author Furmanik, Malgorzata author Laycock, Joanne author Long, David A author Shroff, Rukshana author Shanahan, Catherine M author 2019-04 Children on dialysis have a cardiovascular mortality risk equivalent to older adults in the general population, and rapidly develop 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 ataxia-telangiectasia mutated (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. Sanchis P, Ho CY, Liu Y, Beltran LE, Ahmad S, Jacob AP, et al. Arterial inflammaging drives vascular calcification in children on dialysis. Kidney Int. 2019 Apr;95(4):958-72. Epub 2019 Mar 1. 0085-2538 http://hdl.handle.net/20.500.13003/17563 https://hdl.handle.net/20.500.12105/22693 30827513 10.1016/j.kint.2018.12.014 1523-1755 Kidney International 2-s2.0-85062145445 461924600026 L2001637384 Aging Calcification Dialysis Senescence Vascular smooth muscle cells Arterial inflammaging drives vascular calcification in children on dialysis