Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice.
Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice.
复制标题
普拉格雷可抑制小鼠锂诱导的肾性尿崩症的发展。
DOI：
10.1007/s11302-017-9555-6
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发表时间：
2017
影响因子：
3.5
通讯作者：
Kishore,BellamkondaK
中科院分区：
文献类型：
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作者：
Zhang,Yue;Peti-Peterdi,János;Brandes,AnnaU;Riquier-Brison,Anne;Carlson,NoelG;Müller,ChristaE;Ecelbarger,CarolynM;Kishore,BellamkondaK
以前，我们在啮齿动物肾脏中定位了ADP激活的P2 Y12受体（R），并表明硫酸氢氯吡格雷（CLPD）阻断该受体可减轻锂（Li）诱导的肾源性尿崩症（NDI）。在这里，我们评估了普拉格雷（PRSG）给药对锂诱导的NDI小鼠的影响。CLPD和PRSG均属于噻吩并吡啶类ADP受体拮抗剂。对年龄匹配的成年雄性B6 D2小鼠组（N= 5只/组）喂食常规啮齿动物饲料（CNT）或添加LiCl（40 mmol/kg饲料）或饮用水中的PRSG（10 mg/kg bw/天）或LiCl和PRSG的组合14天，然后实施安乐死。测定水摄入量和尿排出量，并收集和分析血液和肾组织。PRSG管理完全抑制锂诱导的多饮和多尿，并显着防止锂诱导的肾皮质和髓质中AQP 2蛋白丰度的下降。然而，PRSG单独或与Li组合对皮质和/或髓质中NKCC 2或NCC的蛋白丰度没有显著影响。免疫荧光显微镜显示，PRSG管理防止锂诱导的改变，在髓质集合管中的AQP 2蛋白的细胞配置。血清Li、Na和渗透压不受PRSG给药的影响。与CLPD相似，PRSG给药对Li诱导的尿Na排泄增加无影响。然而，与CLPD，PRSG没有增加锂诱导的尿精氨酸加压素（AVP）排泄增加。总之，这些数据表明，噻吩并吡啶类药物对P2 Y12-R的药理学抑制可能在Li诱导的NDI中提供治疗益处。
Previously, we localized ADP-activated P2Y12receptor (R) in rodent kidney and showed that its blockade by clopidogrel bisulfate (CLPD) attenuates lithium (Li)-induced nephrogenic diabetes insipidus (NDI). Here, we evaluated the effect of prasugrel (PRSG) administration on Li-induced NDI in mice. Both CLPD and PRSG belong to the thienopyridine class of ADP receptor antagonists. Groups of age-matched adult male B6D2 mice (N= 5/group) were fed either regular rodent chow (CNT), or with added LiCl (40 mmol/kg chow) or PRSG in drinking water (10 mg/kg bw/day) or a combination of LiCl and PRSG for 14 days and then euthanized. Water intake and urine output were determined and blood and kidney tissues were collected and analyzed. PRSG administration completely suppressed Li-induced polydipsia and polyuria and significantly prevented Li-induced decreases in AQP2 protein abundance in renal cortex and medulla. However, PRSG either alone or in combination with Li did not have a significant effect on the protein abundances of NKCC2 or NCC in the cortex and/or medulla. Immunofluorescence microscopy revealed that PRSG administration prevented Li-induced alterations in cellular disposition of AQP2 protein in medullary collecting ducts. Serum Li, Na, and osmolality were not affected by the administration of PRSG. Similar to CLPD, PRSG administration had no effect on Li-induced increase in urinary Na excretion. However, unlike CLPD, PRSG did not augment Li-induced increase in urinary arginine vasopressin (AVP) excretion. Taken together, these data suggest that the pharmacological inhibition of P2Y12-R by the thienopyridine group of drugs may potentially offer therapeutic benefits in Li-induced NDI.