Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice.
Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice.
复制标题
氯吡格雷可减弱锂诱导的小鼠肾水和钠通道/转运蛋白的改变。
DOI：
10.1007/s11302-015-9469-0
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发表时间：
2015
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;Heiney,KristinaM;Riquier-Brison,Anne;Carlson,NoelG;Müller,ChristaE;Ecelbarger,CarolynM;Kishore,BellamkondaK
锂（Li）给药导致肾脏水通道蛋白和钠通道/转运蛋白的表达和功能紊乱，导致肾源性尿崩症（NDI）。细胞外核苷酸（ATP/ADP/UTP）通过P2受体调节这些转运功能。本研究检测了ADP激活的P2 Y12受体拮抗剂硫酸氢氯吡格雷（CLPD）是否影响锂诱导的肾脏水通道蛋白和钠通道/转运蛋白的改变。成年小鼠用CLPD和/或Li处理14天并安乐死。收集尿液和肾脏进行分析。当与Li一起给药时，CLPD改善了多尿，减弱了尿前列腺素E2（PGE 2）的升高，并导致与Li单独治疗相比显著更高的尿精氨酸加压素（AVP）和醛固酮水平。然而，尿钠排泄量仍然升高。半定量免疫印迹显示，CLPD单独增加肾脏水通道蛋白2（AQP 2），Na-K-2Cl协同转运蛋白（NKCC 2），Na-Cl协同转运蛋白（NCC）和髓质上皮Na通道亚单位（ENaC）25- 130%。当与Li联合使用时，CLPD阻止AQP 2、Na-K-ATP酶和NKCC 2的下调，但对皮质α-或γ-ENaC（70 kDa条带）的下调效果较差。因此，CLPD主要衰减锂诱导的蛋白质参与水的保护（AVP敏感）的下调，与醛固酮敏感性蛋白质的适度影响可能解释持续尿钠排泄。共聚焦免疫荧光显微镜显示近端小管刷状缘和皮质血管中P2 Y12-R的强标记，而髓质粗升支和集合管中P2 Y12-R的弱标记。因此，CLPD有可能直接作用于小管部位，介导这些效应。总之，P2 Y12-R可能代表Li诱导的NDI的新的治疗靶点。
Lithium (Li) administration causes deranged expression and function of renal aquaporins and sodium channels/transporters resulting in nephrogenic diabetes insipidus (NDI). Extracellular nucleotides (ATP/ADP/UTP), via P2 receptors, regulate these transport functions. We tested whether clopidogrel bisulfate (CLPD), an antagonist of ADP-activated P2Y12receptor, would affect Li-induced alterations in renal aquaporins and sodium channels/transporters. Adult mice were treated for 14 days with CLPD and/or Li and euthanized. Urine and kidneys were collected for analysis. When administered with Li, CLPD ameliorated polyuria, attenuated the rise in urine prostaglandin E2 (PGE2), and resulted in significantly higher urinary arginine vasopressin (AVP) and aldosterone levels as compared to Li treatment alone. However, urine sodium excretion remained elevated. Semi-quantitative immunoblotting revealed that CLPD alone increased renal aquaporin 2 (AQP2), Na-K-2Cl cotransporter (NKCC2), Na-Cl cotransporter (NCC), and the subunits of the epithelial Na channel (ENaC) in medulla by 25–130 %. When combined with Li, CLPD prevented downregulation of AQP2, Na-K-ATPase, and NKCC2 but was less effective against downregulation of cortical α- or γ-ENaC (70 kDa band). Thus, CLPD primarily attenuated Li-induced downregulation of proteins involved in water conservation (AVP-sensitive), with modest effects on aldosterone-sensitive proteins potentially explaining sustained natriuresis. Confocal immunofluorescence microscopy revealed strong labeling for P2Y12-R in proximal tubule brush border and blood vessels in the cortex and less intense labeling in medullary thick ascending limb and the collecting ducts. Therefore, there is the potential for CLPD to be directly acting at the tubule sites to mediate these effects. In conclusion, P2Y12-R may represent a novel therapeutic target for Li-induced NDI.