Uremic mouse model to study vascular calcification and “inflamm-aging”

Abstract

Calcification and chronic inflammation of the vascular wall is a high-risk factor for cardiovascular mortality, especially in patients with chronic uremia. For the reduction or prevention of rapid disease progression, no specific treatment options are currently available. This study aimed to evaluate an adenine-based uremic mouse model for studying medial vessel calcification and senescence-associated secretory phenotype (SASP) changes of aortic tissue to unravel molecular pathogenesis and provide a model for therapy testing. The dietary adenine administration induced a stable and similar degree of chronic uremia in DBA2/N mice with an increase of uremia blood markers such as blood urea nitrogen, calcium, creatinine, alkaline phosphatase, and parathyroid hormone. Also, renal fibrosis and crystal deposits were detected upon adenine feeding. The uremic condition is related to a moderate to severe medial vessel calcification and subsequent elastin disorganization. In addition, expression of osteogenic markers as Bmp-2 and its transcription factor Sox-9 as well as p21 as senescence marker were increased in uremic mice compared to controls. Pro-inflammatory uremic proteins such as serum amyloid A, interleukin (Il)-1β, and Il-6 increased. This novel model of chronic uremia provides a simple method for investigation of signaling pathways in vascular inflammation and calcification and therefore offers an experimental basis for the development of potential therapeutic intervention studies. Graphical abstract

LPS-induced senescence of macrophages aggravates calcification and senescence of vascular smooth muscle cells via IFITM3

“…Vascular calcification acts as a complex inflammatory pathology in CKD. Accumulating reports indicated that patients with CKD are exposed to numerous uremic toxins and significantly elevated phosphate, which drives cellular calcification [ 30 , 31 ]. Hyperphosphatemia also unbalanced the oxidant/antioxidant process, which leads to vascular senescence and potentiates vascular inflammation [ 32 ].…”

The functional role of cellular senescence during vascular calcification in chronic kidney disease

“…This was accompanied by a downregulation of the osteogenic marker, osterix ( 26 ). Furthermore, the pro-inflammatory secretome (SASP) derived from senescent cells has been found to elevate in both uremic mouse models and patients ( 58 , 59 ). However, the direct impact of SASP on vascular cells remains underexplored, with potential mechanisms possibly involving the propagation of senescence or amplification of localized inflammation.…”

Pathogenesis and Mechanism of Uremic Vascular Calcification

“…Subsequently, this model was constructed using mice with a modified diet containing casein to maintain appetite [ 24 ]. Tölle et al fed female DBA2/N mice with an adenine diet containing 2% adenine, 6% protein, 1% calcium, and 1% phosphorus and observed gradual calcification of the vascular walls of the abdominal aorta, renal artery, and most prominently the thoracic aorta starting from week 9 [ 25 ]. Similarly, Zhang et al noted large-vessel calcification in the adenine mouse model, along with calcification of the heart valve and glomerular and tubular basement membranes.…”