P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus.
P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus.
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DOI：
10.1681/asn.2014010118
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发表时间：
2015-04
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通讯作者：
Yue Zhang;J. Peti-Peterdi;C. Müller;N. Carlson;Younis Baqi;D. Strasburg;K. Heiney;Karie G. Villanueva;D. Kohan;B. Kishore
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作者：
Yue Zhang;J. Peti-Peterdi;C. Müller;N. Carlson;Younis Baqi;D. Strasburg;K. Heiney;Karie G. Villanueva;D. Kohan;B. Kishore
P2Y12受体(P2Y12-R)信号通过胃肠道介导，最终降低细胞内cAMP水平。由于cAMP是精氨酸加压素(AVP)诱导的肾脏集合管(CD)水运输的中枢调节剂，我们推测如果在CD中表达，P2Y12-R可能在健康人和肾源性尿崩症的肾脏对水的处理中发挥作用。我们在大鼠肾脏中发现了P2Y12-RmRNA的表达，并将其蛋白和水通道蛋白-2(AQP2)免疫定位于CD主细胞。给予不可逆的P2Y12-R抑制剂氯吡格雷硫酸氢能显著增加SD大鼠的尿液浓度和肾脏中的AQP2蛋白。值得注意的是，氯吡格雷没有改变缺乏AVP的Brattleboro大鼠的尿液浓度。氯吡格雷还可显著改善锂诱导的多尿，改善尿液浓缩能力和AQP2蛋白丰度，逆转锂诱导的游离水排泄增加，而不降低血或肾组织锂水平。氯吡格雷还可增加锂诱导的尿AVP排泄增加，抑制锂诱导的尿硝酸盐/亚硝酸盐(一氧化氮产生)和8-异前列腺素(氧化应激)增加。此外，可逆性拮抗剂PSB-0739选择性阻断原代培养的大鼠内髓CD细胞的P2Y12-R，可增强AQP2和AQP3mRNA的表达，以及DDAVP(去氨加压素)诱导的cAMP的产生。综上所述，药物阻断肾脏P2Y12-R可通过增强AVP对肾脏的作用而增加尿浓缩能力，并通过增强AVP对CD的作用而改善锂诱导的NDI。这一策略可能为锂诱导的NDI提供一种新的有效的治疗方法。
P2Y12 receptor (P2Y12-R) signaling is mediated through Gi, ultimately reducing cellular cAMP levels. Because cAMP is a central modulator of arginine vasopressin (AVP)-induced water transport in the renal collecting duct (CD), we hypothesized that if expressed in the CD, P2Y12-R may play a role in renal handling of water in health and in nephrogenic diabetes insipidus. We found P2Y12-R mRNA expression in rat kidney, and immunolocalized its protein and aquaporin-2 (AQP2) in CD principal cells. Administration of clopidogrel bisulfate, an irreversible inhibitor of P2Y12-R, significantly increased urine concentration and AQP2 protein in the kidneys of Sprague-Dawley rats. Notably, clopidogrel did not alter urine concentration in Brattleboro rats that lack AVP. Clopidogrel administration also significantly ameliorated lithium-induced polyuria, improved urine concentrating ability and AQP2 protein abundance, and reversed the lithium-induced increase in free-water excretion, without decreasing blood or kidney tissue lithium levels. Clopidogrel administration also augmented the lithium-induced increase in urinary AVP excretion and suppressed the lithium-induced increase in urinary nitrates/nitrites (nitric oxide production) and 8-isoprostane (oxidative stress). Furthermore, selective blockade of P2Y12-R by the reversible antagonist PSB-0739 in primary cultures of rat inner medullary CD cells potentiated the expression of AQP2 and AQP3 mRNA, and cAMP production induced by dDAVP (desmopressin). In conclusion, pharmacologic blockade of renal P2Y12-R increases urinary concentrating ability by augmenting the effect of AVP on the kidney and ameliorates lithium-induced NDI by potentiating the action of AVP on the CD. This strategy may offer a novel and effective therapy for lithium-induced NDI.