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Arterial "inflammaging" drives vascular calcification in children on dialysis
Pilar Sanchis1, Chin Yee Ho1, Yiwen Liu1
1British Heart Foundation Centre of Excellence, Cardiovascular Division, King's College London, London, UK.
Insights
Children on dialysis experience premature vascular aging, leading to medial vascular calcification. Targeting DNA damage signaling or senescent cells may prevent this in advanced chronic kidney disease (CKD).
Area of Science:
- Cardiovascular Biology
- Nephrology
- Aging Research
Background:
- Children on dialysis face high cardiovascular mortality and medial vascular calcification, similar to older adults.
- Advanced chronic kidney disease (CKD) in children is linked to premature vascular aging and calcification.
- Oxidative DNA damage and senescence markers are elevated in vessels of children with CKD, especially those on dialysis.
Purpose of the Study:
- To investigate the role of premature vascular aging in calcification among children with advanced CKD.
- To explore the mechanisms linking DNA damage, senescence, and vascular calcification in pediatric CKD.
- To assess the clinical relevance of these findings in children undergoing dialysis.
Main Methods:
- Analysis of oxidative DNA damage and senescence markers (p16, p21) in children's vessels.
- Ex vivo treatment of vessel rings with calcifying media.
- Culture and treatment of vascular smooth muscle cells (VSMCs) from children with CKD.
- Assessment of DNA damage repair, senescence, osteogenic differentiation, and SASP activation in VSMCs.
- Inhibition of ATM-mediated DNA damage signaling.
- Clinical correlation of circulating SASP factors with vascular stiffness and calcification.
Main Results:
- Vessels from children with Stage 5 CKD showed increased oxidative DNA damage and senescence markers.
- VSMCs from children on dialysis exhibited persistent DNA damage, impaired repair, accelerated senescence, and increased calcification under calcifying conditions.
- Senescence-associated secretory phenotype (SASP) activation correlated with inflammation and calcification.
- ATM inhibition reduced inflammation and calcification.
- Elevated circulating SASP factors in children on dialysis correlated with vascular stiffness and coronary artery calcification.
Conclusions:
- Dysregulated mineral metabolism in CKD drives vascular "inflammaging" through oxidative DNA damage, premature senescence, and pro-inflammatory SASP activation.
- Targeting DNA damage signaling pathways or senescent cells offers potential therapeutic strategies to prevent vascular calcification in pediatric CKD.
- Premature vascular aging is a key contributor to cardiovascular complications in children with advanced CKD.
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.