Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end-products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD-MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT-711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT-711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT-711, with parallel decreases in left ventricular hypertrophy. ALT-711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT-711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD-MBD with an AGE breaker ALT-711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT-711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD-MBD. © 2019 American Society for Bone and Mineral Research.

中文翻译：

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晚期糖基化终产物 (AGE) 降低药物 ALT-711 对 CKD-MBD 大鼠模型生化、血管和骨参数的影响。


慢性肾病-矿物质骨病 (CKD-MBD) 是一种全身性疾病，影响骨和矿物质稳态、血管钙化和骨骼的血液测量。我们假设 CKD 中晚期糖基化终末产物 (AGE) 的积累可能通过胶原蛋白的改变导致血管和骨病理。我们使用正常剂量和高剂量的 AGE 交联破坏剂群 (ALT-711) 或饮用水中的钙来模拟磷酸钙结合剂，治疗自然发生的 CKD-MBD 模型（Cy/+ 大鼠）10 周。将这些动物与未治疗的正常（NL）动物进行比较。结果显示，与正常动物相比，CKD 动物的血尿素氮 (BUN)、PTH、FGF23 和磷升高。 ALT-711 治疗对肾功能或 PTH 没有影响，但 3 mg/kg 会降低 FGF23，而钙会降低 PTH。与 NL 动物相比，CKD 动物的主动脉血管钙化生化评估增加，并且通过正常但高剂量的 ALT-711 可以减少，同时左心室肥厚也相应减少。 ALT-711 (3 mg/kg) 不会改变主动脉 AGE 含量，但会降低主动脉晚期糖基化终末产物 (RAGE) 和 NADPH 氧化酶 2 (NOX2) 受体的表达，表明与细胞水平氧化应激减少有关。 3 mg/kg ALT-711 使升高的总骨 AGE 降低，钙治疗降低了骨 AGE 和皮质孔隙度，但只有钙改善了骨特性。总之，用 AGE 抑制剂 ALT-711 治疗 CKD-MBD，可减少 FGF23、减少主动脉钙化并减少总骨 AGE，但骨力学没有改善。这些结果表明 ALT-711 对胶原蛋白影响不大，但有潜在的细胞影响。 这些数据还强调需要在组织水平上更好地测量特定类型的 AGE 蛋白，以便充分阐明 AGE 对 CKD-MBD 的影响。 © 2019 美国骨与矿物质研究学会。