Clinical and experimental studies have reported that
phosphate overload plays a central role in the pathogenesis of
vascular calcification in
chronic kidney disease. However, it remains undetermined whether
phosphate induces cellular senescence during
vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3%
adenine that showed more slowly progressive
kidney failure, more robust
vascular calcification, and longer survival than the conventional model (0.75%
adenine). To determine the effect of
phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of
phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified
adenine-based diet (CKD); (3) CKD rats treated with 6%
lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6%
calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased
protein expression of senescence-associated β-
galactosidase, bone-related
proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both
phosphate binders. However, serum levels of oxidative stress and inflammatory
markers, serum fibroblast growth factor 23, and aortic
calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion,
phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and
phosphate binders can prevent both cellular senescence and calcification of VSMCs via
phosphate unloading. Our modified
adenine-based uremic rat model is useful for evaluating
uremia-related complications, including
vascular calcification.