Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway.
Wnt5a induces renal AQP2 expression by activating calcineurin signalling pathway.
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DOI：
10.1038/ncomms13636
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发表时间：
2016-11-28
影响因子：
16.6
通讯作者：
Uchida S
中科院分区：
文献类型：
--
作者：
Ando F;Sohara E;Morimoto T;Yui N;Nomura N;Kikuchi E;Takahashi D;Mori T;Vandewalle A;Rai T;Sasaki S;Kondo Y;Uchida S
遗传性肾源性尿崩症（NDI）的特征在于肾脏中的尿浓缩机制缺陷，其主要由加压素2型受体的功能丧失突变引起。为了治疗遗传性NDI，需要绕过有缺陷的加压素2型受体的新策略来激活水通道蛋白2（AQP 2）水通道。在这里，我们表明，Wnt 5a调节AQP 2蛋白的表达，磷酸化和运输，这表明Wnt 5a是一种内源性配体，可以调节AQP 2的经典加压素/cAMP信号通路的激活。在NDI小鼠模型中，Wnt 5a成功地增加了AQP 2的顶膜定位和尿渗透压。我们还证明，钙调神经磷酸酶是Wnt 5a诱导的AQP 2激活的关键调节因子，而不影响细胞内cAMP水平和PKA活性。钙调神经磷酸酶的重要性进一步证实了其激活剂，花生四烯酸，这表明加压素样作用强调钙调神经磷酸酶激活剂可能是遗传性NDI的潜在治疗靶点。 水通道AQP 2介导肾脏中尿液的浓度。Ando等人在此表明，Wnt 5通过激活钙调蛋白/钙调神经磷酸酶信号通路调节AQP 2表达和定位，从而促进集合管通透性。
Heritable nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentration mechanisms in the kidney, which are mainly caused by loss-of-function mutations in the vasopressin type 2 receptor. For the treatment of heritable NDI, novel strategies that bypass the defective vasopressin type 2 receptor are required to activate the aquaporin-2 (AQP2) water channel. Here we show that Wnt5a regulates AQP2 protein expression, phosphorylation and trafficking, suggesting that Wnt5a is an endogenous ligand that can regulate AQP2 without the activation of the classic vasopressin/cAMP signalling pathway. Wnt5a successfully increases the apical membrane localization of AQP2 and urine osmolality in an NDI mouse model. We also demonstrate that calcineurin is a key regulator of Wnt5a-induced AQP2 activation without affecting intracellular cAMP level and PKA activity. The importance of calcineurin is further confirmed with its activator, arachidonic acid, which shows vasopressin-like effects underlining that calcineurin activators may be potential therapeutic targets for heritable NDI. The water channel AQP2 mediates the concentration of urine in the kidney. Here Ando et al. show that Wnt5 promotes collecting duct permeability by regulating AQP2 expression and localization through activation of the calmodulin/calcineurin signalling pathway.
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影响因子：
4
作者：
Gooch, Jennifer L.;Guler, Rebecca L.;Toro, Juan J.
通讯作者：
Toro, Juan J.
DOI：
10.1152/ajprenal.00052.2014
发表时间：
2015-03-01
影响因子：
4.2
作者：
Jung, Hyun Jun;Kim, Sang-Yeob;Kwon, Tae-Hwan
通讯作者：
Kwon, Tae-Hwan
影响因子：
4.8
作者：
Ma, Li;Wang, Hsien-yu
通讯作者：
Wang, Hsien-yu
DOI：
10.1152/ajprenal.00330.2013
发表时间：
2014-02-01
影响因子：
4.2
作者：
Miranda, Carlos A.;Lee, Jae Wook;Knepper, Mark A.
通讯作者：
Knepper, Mark A.
影响因子：
5.3
作者：
Dejmek, Janna;Safholm, Annette;Leandersson, Karin
通讯作者：
Leandersson, Karin