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, 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.

Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate

“…Similarly, chronic mineral loading of ECM with calcium, phosphate and uremic toxins may ultimately trigger immune cell-dependent "inflammaging" thus driving e.g. arterial calcification in children on dialysis [73].…”

Research Models for Studying Vascular Calcification

“…Currently, aortic rings from rats and mice are commonly used for studying vessel calcification under various conditions. The stimulation time varies from 3-14 days [6,24,25,28,59,[62][63][64][65]. Although the utilization of aortic rings comes closer to the physiologic setting, a multitude of influencing factors is still lost.…”

“…One pivotal point of VC is probably the vascular smooth muscle cell (VSMC) with its phenotype changes ending in vessel mineralization [2]. The phenotype shift of VSMC seems to be induced by a variety of conditions such as inflammation [3], reactive oxygen species (ROS) [4,5] and senescence [6]. Aside from differentiated VSMC, other cell types are associated with VC.…”

Accelerated and intensified calcific atherosclerosis and microvascular dysfunction in patients with chronic kidney disease

“…The prevalence of medial calcification appears to be similar among patients with CKD as in the general population; however this may be a function of older age, i.e. in younger matched cohorts those on dialysis would have higher rates of medial calcification (Chin et al, 2017;Nakamura et al, 2009;Sanchis et al, 2019). Modern intravascular imaging modalities (Chin et al, 2017) will allow for greater delineation of characteristic calcification patterns in patients with CKD.…”