Aquaporin-11 knockout mice and polycystic kidney disease animals share a common mechanism of cyst formation
Aquaporin-11 knockout mice and polycystic kidney disease animals share a common mechanism of cyst formation
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DOI：
10.1096/fj.08-111872
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Abe, Keiko
中科院分区：
文献类型：
--
作者：
Okada, Shinji;Misaka, Takumi;Abe, Keiko
水通道蛋白-11 (AQP11) 是水通道蛋白家族的新成员，定位于内质网 (ER)。 Aqp11(-/-) 小鼠新生儿患有来自近端小管的多囊肾。它的发生是通过内质网的空泡化来进行的。然而，空泡和囊肿形成的机制仍有待阐明。在这里，我们发现 Aqp11(-/-) 小鼠和多囊肾病 (PKD) 动物具有共同的囊肿形成致病机制。我们进行了微阵列分析和组织化学染色，以表征 Aqp11 破坏对 1 周龄小鼠肾脏的影响。微阵列分析显示，Aqp11(-/-) 小鼠中显着变化的功能类别与 PKD 动物中的类似。组织化学研究显示 Myc、Egfr、Egf 3 个基因的表达变化，这些基因被认为与 PKD 中囊性细胞的增殖有关。我们实际上证实了具有空泡化ER的近曲小管细胞中细胞增殖的激活。此外，与细胞外基质重塑相关的三个基因 Mmp12、Timp1、Tgfb1 在成纤维细胞中上调。我们还证明了在具有空泡内质网的近曲小管细胞中通过内质网应激途径激活细胞凋亡。这些结果为 AQP11 的生理作用提供了新的见解。
Aquaporin-11 (AQP11), a new member of the aquaporin family, is localized in the endoplasmic reticulum (ER). Aqp11(-/-) mice neonatally suffer from polycystic kidneys derived from the proximal tubule. Its onset is proceeded by the vacuolization of ER. However, the mechanism for the formation of vacuoles and cysts remains to be clarified. Here, we show that Aqp11(-/-) mice and polycystic kidney disease (PKD) animals share a common pathogenic mechanism of cyst formation. We performed microarray analyses and histochemical staining to characterize the effects of the disruption of Aqp11 on kidneys of 1-wk-old mice. Microarray analyses revealed that the significantly changed functional categories in Aqp11(-/-) mice were similar to those in PKD animals. Histochemical studies showed expression changes of 3 genes, Myc, Egfr, Egf, which are assumed to be involved in the proliferation of cystic cells in PKD. We actually confirmed the activation of cell proliferation in the proximal tubule cells with vacuolized ER. Furthermore, three genes associated with the remodeling of the extracellular matrix, Mmp12, Timp1, Tgfb1, were up-regulated in the fibroblasts. We also demonstrated the activation of apoptosis via the ER-stress pathway in the proximal tubule cells with vacuolized ER. These results provide new insights into the physiological roles of AQP11.