Novel activators of aquaporin 2 membrane expression for the treatment of nephrogenic diabetes insipidus: less is more. Focus on "High-throughput chemical screening identifies AG-490 as a stimulator of aquaporin 2 membrane expression and urine concentratio
Novel activators of aquaporin 2 membrane expression for the treatment of nephrogenic diabetes insipidus: less is more. Focus on "High-throughput chemical screening identifies AG-490 as a stimulator of aquaporin 2 membrane expression and urine concentratio
复制标题
用于治疗肾性尿崩症的水通道蛋白 2 膜表达的新型激活剂：少即是多。
DOI：
10.1152/ajpcell.00184.2014
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Blount,MitsiA
中科院分区：
文献类型：
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作者：
Sands,JeffM;Blount,MitsiA
肾性尿崩症 (NDI) 是一种以因肾脏无法对加压素作出反应而产生大量稀尿为特征的疾病 (9)。在美国，每年约有 41,000 人被诊断患有 NDI。 NDI 可由先天性或后天性病因引起。 2 型加压素受体 (V 2 R) 突变发生在 90% 的先天性 NDI 家族（突变已知）中，而水通道蛋白 2 (AQP2) 水通道突变则发生在另外 10% 的家族中 (9)。先天性 NDI 对患有这种疾病的儿童产生深远的影响，他们每天产生多达 20 升尿液，因此每天必须喝 20 升水以避免脱水。多次严重脱水的儿童通常会出现智力低下 (1)。然而，通过摄入足够的水来防止脱水，可以预防智力低下 (1)。获得性 NDI 可由多种原因引起，最常见的是长期使用锂，锂是一种干扰 cAMP 产生和信号传导的药物，用于治疗双相情感障碍 (10)。AQP2 会响应加压素而增加集合管顶端质膜的水渗透性，从而在存在渗透梯度的情况下促进水的重吸收 (3)。 AQP2 有四个加压素敏感的磷酸化位点：S256、S261、S264 和 S269。 S256 和 S261 均参与 AQP2 向顶端质膜的运输。 S269 的磷酸化对于 AQP2 在顶端质膜中的保留很重要。在患有 V 2 R 突变或服用锂的患者中，AQP2 没有突变，这表明如果有可能增加 AQP2 的顶端质膜积累和功能，而不依赖于加压素，则可能能够治疗 NDI，或至少减轻 NDI 的严重程度。
nephrogenic diabetes insipidus (NDI) is a disease characterized by the production of very large quantities of dilute urine resulting from an inability of the kidney to respond to vasopressin (9). In the US, approximately 41,000 people are diagnosed with NDI each year. NDI can result from either congenital or acquired etiologies. Mutations in the type 2 vasopressin receptor (V 2 R) occur in 90% of families (in which the mutation is known) with congenital NDI and in the aquaporin 2 (AQP2) water channel in the other 10%(9). Congenital NDI has a profound impact on children with the disease who produce up to 20 liters of urine per day and thus must drink 20 liters of water daily to avoid dehydration. Children who suffer multiple episodes of severe dehydration often end up with mental retardation (1). However, mental retardation can be prevented with adequate water intake to prevent dehydration (1). Acquired NDI can result from multiple causes, most commonly by chronic use of lithium, a medication that interferes with cAMP production and signaling, and which is used to treat bipolar disorders (10).AQP2 increases the water permeability of the collecting duct apical plasma membrane in response to vasopressin, facilitating water reabsorption in the presence of an osmotic gradient (3). AQP2 has four vasopressin-sensitive phosphorylation sites: S256, S261, S264, and S269. Both S256 and S261 are involved in AQP2 trafficking to the apical plasma membrane. Phosphorylation at S269 is important for AQP2 retention in the apical plasma membrane. In patients with V 2 R mutations or taking lithium, there are no mutations in AQP2, suggesting that if it were possible to increase AQP2's apical plasma membrane accumulation and function, independent of vasopressin, one might be able to treat, or at least lessen the severity of, the NDI.