Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet
Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet
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DOI：
10.1016/j.ajpath.2020.10.012
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发表时间：
2021-01-29
影响因子：
6
通讯作者：
Takahashi, Nobuyuki
中科院分区：
文献类型：
--
作者：
Oe, Yuji;Mitsui, Shohei;Takahashi, Nobuyuki
异位钙化是慢性肾脏病（CKD）患者心血管疾病的危险因素，而内皮型一氧化氮合酶（eNOS）受损与CKD并发症有关。然而，eNOS功能障碍是否是CKD异位钙化的原因仍有待阐明。为了解决这个问题，我们研究了eNOS在腺嘌呤和高磷（Ade + HP）饮食引起的肾损伤小鼠异位钙化中的作用。DBA/2 J小鼠是一种钙化敏感品系，喂食Ade thorn HP 3周。在钙化的主动脉中eNOS相关基因的表达水平显著降低。C57 BL/6 J是一种抗钙化的品系，当给予Ade thorn HP饮食4周时，野生型小鼠在主动脉和肾脏中显示出轻度钙化病变。相反，eNOS缺乏导致严重的主动脉钙化，并伴随着一种骨软骨形成标记物--侏儒相关转录因子2的增加。在缺乏eNOS喂养的Ade thorn HP的小鼠中，肾钙沉积和肾小管损伤评分显著增加。eNOS缺乏导致异位钙化加重与氧化应激标志物如烟酰胺腺嘌呤二核苷酸磷酸氧化酶增加有关。总之，eNOS在预防异位钙化中至关重要。因此，维持eNOS有助于减少心血管疾病事件并改善CKD患者的预后。
Ectopic calcification is a risk of cardiovascular disease in chronic kidney disease (CKD) patients, and impaired endothelial nitric oxide synthase (eNOS) is involved in the CKD complications. However, whether eNOS dysfunction is a cause of ectopic calcification in CKD remains to be elucidated. To address this issue, we investigated the role of eNOS in ectopic calcification in mice with renal injury caused by an adenine and high-phosphorus (Ade + HP) diet. DBA/2J mice, a calcification-sensitive strain, were fed Ade thorn HP for 3 weeks. Expression levels of eNOS-related genes were reduced significantly in their calcified aorta. C57BL/6J is a calcification-resistant strain, and wild-type mice showed mild calcified lesions in the aorta and kidney when given an Ade thorn HP diet for 4 weeks. In contrast, a lack of eNOS led to the development of severe aortic calcification accompanied by an increase in runt-related transcription factor 2, an osteochondrogenic marker. Increased renal calcium deposition and the tubular injury score were remarkable in mice lacking eNOS-fed Ade thorn HP. Exacerbation of ectopic calcification by a lack of eNOS is associated with increased oxidative stress markers such as nicotinamide adenine dinucleotide phosphate oxidases. In conclusion, eNOS is critically important in preventing ectopic calcification. Therefore, the maintenance of eNOS is useful to reduce cardiovascular disease events and to improve prognosis in CKD patients.