Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation
Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation
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DOI：
10.1073/pnas.0602331103
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发表时间：
2006-09-19
影响因子：
11.1
通讯作者：
Uchida, Shinichi
中科院分区：
文献类型：
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作者：
Sohara, Eisei;Rai, Tatemitsu;Uchida, Shinichi
水通道蛋白2 (AQP2) C端框架移位突变导致常染色体显性肾源性尿崩症（AD-NDI）。为了在体内确定这种疾病的分子机制并测试可能的治疗策略，我们产生了AQP2 （763-772 del）敲入突变小鼠。杂合子敲入小鼠的尿浓缩能力严重受损。然而，他们能够在脱水后稍微增加尿液渗透压。与常染色体隐性NDI相比，这种温和的表型是人类AD-NDI的一个特征，因此表明AD-NDI小鼠模型的成功建立。AD-NDI小鼠收集管细胞的免疫荧光显示，AQP2突变体被错选到基底外侧，而不是顶端质膜。此外，突变体AQP2与野生型AQP2形成异聚物，即使在脱水条件下，对野生型AQP2的正常顶端分选也表现出显性负向影响。使用这种敲入小鼠，我们测试了几种治疗AD-NDI的药物，发现罗利普兰（一种磷酸二酯酶4抑制剂）能够增加尿液渗透压。因此，磷酸二酯酶抑制剂可能是治疗AD-NDI的有用药物。该动物模型表明，突变单体获得显性负作用，逆转了多聚体的正常极化分选。
Frame-shift mutations within the C terminus of aquaporin 2 (AQP2) cause autosomal-dominant nephrogenic diabetes insipidus (AD-NDI). To identify the molecular mechanism(s) of this disease in vivo and to test possible therapeutic strategies, we generated a mutant AQP2 (763-772 del) knockin mouse. Heterozygous knockin mice showed a severely impaired urine-concentrating ability. However, they were able to slightly increase urine osmolality after dehydration. This milder phenotype, when compared with autosomal-recessive NDI, is a feature of AD-NDI in humans, thus suggesting successful establishment of an AD-NDI mouse model. lmmunofluorescence of collecting duct cells in the AD-NDI mouse revealed that the mutant AQP2 was missorted to the basolateral instead of apical plasma membrane. Furthermore, the mutant AQP2 formed a heterooligomer with wild-type AQP2 and showed a dominant-negative effect on the normal apical sorting of wild-type AQP2 even under dehydration. Using this knockin mouse, we tested several drugs for treatment of AD-NDI and found that rolipram, a phosphodiesterase 4 inhibitor, was able to increase urine osmolality. Phosphodiesterase inhibitors may thus be useful drugs for the treatment of AD-NDI This animal model demonstrates that a mutant monomer gains a dominant-negative effect that reverses the normal polarized sorting of multimers.