Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus.
Targeting renal purinergic signalling for the treatment of lithium-induced nephrogenic diabetes insipidus.
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靶向肾嘌呤能信号传导，用于治疗锂诱导的肾脏基因糖尿病。
DOI：
10.1111/apha.12507
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发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Kishore BK;Carlson NG;Ecelbarger CM;Kohan DE;Müller CE;Nelson RD;Peti-Peterdi J;Zhang Y
由于锂具有预防自杀倾向的能力，因此它在治疗双相情感障碍方面仍然保持着关键地位。然而，锂的长期使用通常受到肾源性尿崩症（NDI）的发展的限制，这是一种使人衰弱的疾病。锂诱导的NDI是由于肾脏对精氨酸加压素（AVP）的抵抗，导致多尿、尿钠排泄和尿钾排泄。由细胞外核苷酸（ATP/UTP）介导的嘌呤能信号传导，通过P2 Y受体起作用，通过降低细胞cAMP并因此降低AQP 2蛋白水平来对抗AVP对肾集合管（CD）的作用。从这一现象中得到提示，我们发现ATP/UTP激活的P2 Y2受体可能参与了锂诱导的大鼠NDI，并表明P2 Y2受体敲除小鼠对锂诱导的多尿、钠尿和钾尿具有显著抵抗性。这些研究的扩展显示，ADP激活的P2 Y12受体在肾脏中表达，并且通过给予硫酸氢氯吡格雷（Plaidogrel ®）对其进行不可逆阻断可改善啮齿动物中Li诱导的NDI。平行的体外研究表明，可逆拮抗剂PSB-0739阻断P2 Y12受体可使CD对AVP的作用敏感。因此，我们的研究揭示了靶向P2 Y2或P2 Y12受体对抗锂诱导的NDI中AVP抗性的潜在有益作用。如果在进一步的研究中建立，我们的研究结果可能会为开发更好，更安全的方法来治疗NDI铺平道路，从目前的治疗方法，主要是对抗抗AVP作用的那些增强肾脏对AVP作用的敏感性。
Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium-induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP-activated P2Y2 receptor in lithium-induced NDI in rats, and showed that P2Y2 receptor knockout mice are significantly resistant to Li-induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP-activated P2Y12 receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulfate (Plavix®) ameliorates Li-induced NDI in rodents. Parallel in vitro studies showed that P2Y12 receptor blockade by the reversible antagonist PSB-0739 sensitizes CD to the action of AVP. Thus, our studies unraveled the potential beneficial effects of targeting P2Y2 or P2Y12 receptors to counter AVP resistance in lithium-induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti-AVP effects to those that enhance the sensitivity of the kidney to AVP action.
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影响因子：
11.4
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1152/ajprenal.00383.2005
发表时间：
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