Genetic deletion of ADP-activated P2Y12 receptor ameliorates lithium-induced nephrogenic diabetes insipidus in mice.
Genetic deletion of ADP-activated P2Y12 receptor ameliorates lithium-induced nephrogenic diabetes insipidus in mice.
复制标题
ADP 激活的 P2Y12 受体的基因缺失可改善锂诱导的小鼠肾性尿崩症。
DOI：
10.1111/apha.13191
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Kishore,BellamkondaK
中科院分区：
文献类型：
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作者：
Zhang,Yue;Hansson,KennyM;Liu,Tao;Magnell,Kerstin;Huang,Yufeng;Carlson,NoelG;Kishore,BellamkondaK
目的锂在双相情感障碍治疗中的应用受到肾源性尿崩症（NDI）发展的限制。我们报道用氯吡格雷或普拉格雷阻断p2y12受体(R)可显著改善锂离子诱导的啮齿动物NDI。使用基因缺失P2Y12‐R的小鼠，我们评估了P2Y12‐R是否介导了所观察到的改善。方法sp2ry12−/−小鼠系（C57/BL6）是从Deltagen公司生产的敲除（KO）小鼠的冷冻保存胚胎中重新获得的。通过杂合杂交获得的同基因野生型（WT）小鼠进行了近交。各组成年WT和KO小鼠分别饲喂添加锂（40 mmol LiCl/kg食物）或常规饮食，并于2周或4周后安乐死。分析24小时尿液样本和终末期血液和肾脏样本。结果在两个时间点上，锂离子诱导的多尿和肾髓质水通道蛋白2 （AQP2）蛋白丰度的降低在KO小鼠和WT小鼠中都不明显。免疫荧光显微镜显示，锂离子诱导的WT小鼠髓质收集管中AQP2蛋白的细胞配置改变在KO小鼠中被钝化。锂处理后，两种基因型的血清锂、钠和渗透压相似。2周后，锂诱导WT小鼠尿中Na、K和精氨酸加压素的排泄量显著增加，而KO小鼠则没有。综上所述，我们的数据显示，与药物阻断类似，P2Y12‐R的缺失可显著改善锂诱导的NDI，但不会降低血清锂水平。因此，用市场上现有的药物靶向P2Y12‐R为治疗NDI提供了一种新的、更安全的方法。
AimTherapeutic use of lithium in bipolar disorder is limited by the development of nephrogenic diabetes insipidus (NDI). We reported that pharmacological blockade of P2Y12receptor (R) with clopidogrel or prasugrel significantly ameliorated lithium‐induced NDI in rodents. Using mice genetically lacking P2Y12‐R we evaluated whether the observed amelioration is mediated through P2Y12‐RMethodsP2ry12−/−mouse line (C57/BL6) was rederived from cryopreserved embryos of the knockout (KO) mice generated by Deltagen Inc. Syngeneic wild type (WT) mice obtained by heterozygous crossing were inbred. Groups of adult WT and KO mice were fed lithium‐added (40 mmol LiCl/kg food) or regular diet, and euthanized after 2 or 4 weeks. Twenty‐four hour urine samples and terminal blood and kidney samples were analyzed.ResultsAt both time points, lithium‐induced polyuria and decrease in aquaporin‐2 (AQP2) protein abundance in the kidney medulla were less marked in KO vs WT mice. Immunofluorescence microscopy revealed that lithium‐induced alterations in the cellular disposition of AQP2 protein in the medullary collecting ducts of WT mice were blunted in KO mice. Serum lithium, sodium and osmolality were similar in both genotypes after lithium treatment. After 2 weeks, lithium induced marked increases in urinary excretion of Na, K, and arginine vasopressin in WT mice but not in KO mice.ConclusionTaken together, our data show that similar to pharmacological blockade, deletion of P2Y12‐R significantly ameliorates lithium‐induced NDI, without reducing serum lithium levels. Hence, targeting P2Y12‐R with currently available drugs in the market offers a novel and safer method for treating NDI.
DOI：
10.1073/pnas.81.18.5633
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
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作者：
CATHCART, R;SCHWIERS, E;AMES, BN
通讯作者：
AMES, BN
影响因子：
64.8
作者：
KUCHINO, Y;MORI, F;NISHIMURA, S
通讯作者：
NISHIMURA, S