Chen Neal X, Srinivasan Shruthi, O'Neill Kalisha, Nickolas Thomas L, Wallace Joseph M, Allen Matthew R, Metzger Corinne E, Creecy Amy, Avin Keith G, Moe Sharon M
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
J Bone Miner Res. 2020 Mar;35(3):608-617. doi: 10.1002/jbmr.3925. Epub 2019 Dec 30.
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.
慢性肾脏病-矿物质与骨异常（CKD-MBD）是一种系统性疾病，会影响骨与矿物质内稳态、血管钙化及骨骼的血液指标。我们推测，慢性肾脏病中晚期糖基化终产物（AGEs）的蓄积可能通过改变胶原蛋白导致血管和骨骼病变。我们用正常剂量和高剂量的AGE交联断裂剂阿雷吉明（ALT-711），或在饮用水中添加钙以模拟磷酸钙结合剂，对慢性肾脏病-矿物质与骨异常的天然模型Cy/+大鼠进行了为期10周的治疗。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，慢性肾脏病动物的血尿素氮（BUN）、甲状旁腺激素（PTH）、成纤维细胞生长因子23（FGF23）和磷水平升高。ALT-711治疗对肾功能或PTH没有影响，但3mg/kg可降低FGF23，而钙可降低PTH。与NL相比，慢性肾脏病动物经生化评估的主动脉血管钙化增加，正常剂量而非高剂量的ALT-711可使其降低，同时左心室肥厚也相应减轻。ALT-711（3mg/kg）未改变主动脉AGE含量，但降低了晚期糖基化终产物受体（RAGE）和烟酰胺腺嘌呤二核苷酸磷酸氧化酶2（NOX2）在主动脉中的表达，提示其作用与细胞水平氧化应激降低有关。3mg/kg的ALT-711可降低总骨AGE水平，钙治疗可降低骨AGE和皮质骨孔隙率，但只有钙改善了骨骼特性。总之，用AGE裂解剂ALT-711治疗CKD-MBD可降低FGF23、减少主动脉钙化并降低总骨AGE，但未改善骨骼力学性能。这些结果表明ALT-711对胶原蛋白影响不大，但可能有细胞效应。数据还强调需要在组织水平更好地测量特定类型的AGE蛋白，以充分阐明AGEs对CKD-MBD的影响。©2019美国骨与矿物质研究学会。
