PDF(Sci-hub)
Abstract：
Previously, we localized ADP-activated P2Y12 receptor (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.
摘要：
以前,我们在啮齿动物肾脏中定位了ADP激活的P2Y12受体（R），并表明氯吡格雷硫酸氢盐（CLPD）对其阻断可减轻锂（Li）诱导的肾性尿崩症（NDI）。这里,我们评估了普拉格雷（PRSG）给药对Li诱导的小鼠NDI的影响。CLPD和PRSG都属于ADP受体拮抗剂的噻吩并吡啶类。年龄匹配的成年雄性B6D2小鼠组（N=5/组）喂食常规啮齿动物食物（CNT），或在饮用水中加入LiCl（40mmol/kg食物）或PRSG（10mg/kgbw/天）或LiCl和PRSG的组合14天，然后实施安乐死。测定水摄入量和尿量,收集血液和肾组织并进行分析。PRSG给药完全抑制了Li诱导的多饮和多尿，并显着阻止了Li诱导的肾皮质和髓质中AQP2蛋白丰度的降低。然而,PRSG单独或与Li组合对皮质和/或髓质中NKCC2或NCC的蛋白质丰度没有显着影响。免疫荧光显微镜检查显示，PRSG的给药可防止Li诱导的髓样收集管中AQP2蛋白细胞分布的改变。血清Li，Na,和渗透压不受PRSG管理的影响。类似于CLPD,PRSG给药对Li诱导的尿Na排泄增加没有影响。然而,不像CLPD,PRSG不会增加Li诱导的尿精氨酸加压素（AVP）排泄增加。一起来看,这些数据表明,噻吩并吡啶类药物对P2Y12-R的药理抑制作用可能在Li诱导的NDI中提供潜在的治疗益处.
