Vitamin D receptor agonist VS-105 improves cardiac function in the presence of enalapril in 5/6 nephrectomized rats.
Vitamin D receptor agonist VS-105 improves cardiac function in the presence of enalapril in 5/6 nephrectomized rats.
复制标题
维生素 D 受体激动剂 VS-105 在依那普利存在下可改善 5/6 肾切除大鼠的心功能。
DOI：
10.1152/ajprenal.00129.2014
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Wessale,JerryL
中科院分区：
文献类型：
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作者：
Wu-Wong,JRuth;Chen,Yung-Wu;Wessale,JerryL
维生素D受体（VDR）激动剂（VDRA）通常用于治疗继发于慢性肾病（CKD）的甲状旁腺功能亢进。CKD患者的心血管发病率和死亡率风险极高。临床观察显示，VEGFR 2治疗可能与CKD患者的心肾保护和生存获益相关。5/6肾切除（NX）的Sprague-Dawley大鼠建立尿毒症表现出血清甲状旁腺激素（PTH）升高，高血压，和异常的心脏功能。用VS-105（一种新型的维生素A）（0.05和0.5 μg/kg，灌胃）治疗5/6只NX大鼠，每天一次，连续8周，同时加或不加依那普利（30 mg/kg，通过饮用水口服），可有效地抑制血清PTH，而不升高血清钙。VS-105单用与依那普利（174 ± 6 ~ 144 ± 7 mmHg，P< 0.05）同样有效地降低收缩压（174 ± 6 ~ 145 ± 9 mmHg，P< 0.05）。VS-105改善心脏功能参数，如E/A比，射血分数和缩短分数与或不与依那普利。依那普利或VS-105单独使用可显著降低左心室肥厚（LVH）; VS-105加依那普利不能进一步降低LVH。VS-105显著减少心脏和肾脏纤维化。VS-105缺乏高钙毒性是由于其缺乏刺激肠钙转运和诱导肠钙转运蛋白基因如Calb 3和TRPV 6表达的作用。这些研究表明，VS-105是一种新型VDR，可通过VDR激活提供心血管益处。需要临床研究来证实VS-105在CKD中的心血管益处。
Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). Patients with CKD experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRA therapy may be associated with cardio-renal protective and survival benefits in patients with CKD. The 5/6 nephrectomized (NX) Sprague-Dawley rat with established uremia exhibits elevated serum parathyroid hormone (PTH), hypertension, and abnormal cardiac function. Treatment of 5/6 NX rats with VS-105, a novel VDRA (0.05 and 0.5 μg/kg po by gavage), once daily for 8 wk in the presence or absence of enalapril (30 mg/kg po via drinking water) effectively suppressed serum PTH without raising serum calcium. VS-105 alone reduced systolic blood pressure (from 174 ± 6 to 145 ± 9 mmHg,P< 0.05) as effectively as enalapril (from 174 ± 6 to 144 ± 7 mmHg,P< 0.05). VS-105 improved cardiac functional parameters such as E/A ratio, ejection fraction, and fractional shortening with or without enalapril. Enalapril or VS-105 alone significantly reduced left ventricular hypertrophy (LVH); VS-105 plus enalapril did not further reduce LVH. VS-105 significantly reduced both cardiac and renal fibrosis. The lack of hypercalcemic toxicity of VS-105 is due to its lack of effects on stimulating intestinal calcium transport and inducing the expression of intestinal calcium transporter genes such as Calb3 and TRPV6. These studies demonstrate that VS-105 is a novel VDRA that may provide cardiovascular benefits via VDR activation. Clinical studies are required to confirm the cardiovascular benefits of VS-105 in CKD.