Abstract
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.
Highlights
vascular smooth muscle cells (VSMCs) from children on dialysis show elevated levels of DNA damage and premature senescence in vitro VSMCs were explanted from control and CKD stage 5 (CKD5)-5D vessels and compared during serial passaging in vitro
In this study, we show that vessels from children with chronic kidney disease (CKD) exhibited features of premature aging in vivo including oxidative DNA damage and elevated senescence markers, and these aging indices persisted on the culture of VSMCs in vitro
The persistent DNA damage observed in dialysis VSMCs was associated with increased osteogenic differentiation and calcification driven in part, by activation of the proinflammatory senescence-associated secretory phenotype (SASP)
Summary
A key event leading to cellular aging is the accumulation of unrepairable or persistent DNA damage.[8,9] DNA damage increases with age and factors such as oxidative stress can accelerate aging in part, by promoting oxidative DNA damage.[10,11,12] Persistent DNA damage signaling, via key transducers such as the kinase ataxia-telangiectasia mutated (ATM), promotes upregulation of the checkpoint cell cycle inhibitors p16 (CDKN2A/INK4a) or p21 (CDKN1A) or both leading to cell cycle arrest and to cellular senescence.[13] Senescent cells are viable but can no longer contribute to repair processes They display an inflammatory phenotype termed the senescence-associated secretory phenotype (SASP) characterized by the secretion of an array of proinflammatory cytokines and growth factors as well as proteases that can act in a paracrine fashion to influence remote cells and tissues.[14] DNA damage and cellular senescence have recently been reported to promote. Elevated P is associated with increased cardiovascular calcification and mortality in aging populations;[23] the molecular events linking aging and calcification with dysregulated mineral metabolism are not understood
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