Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia
Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia
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DOI：
10.1093/hmg/ddn045
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发表时间：
2008-06-01
影响因子：
3.5
通讯作者：
Igarashi, Peter
中科院分区：
文献类型：
--
作者：
Patel, Vishal;Li, Ling;Igarashi, Peter
多囊肾病（PKD）是一种遗传性疾病，其特征是肾实质囊肿积聚和肾功能进行性下降。最近的研究表明PKD是由初级纤毛的异常引起的。我们之前已经证明，在胚胎发育过程中，生纤毛基因Kif3a的肾特异性失活会产生肾囊肿和肾功能衰竭。在这里，我们使用他莫昔芬诱导的肾脏特异性基因靶向来灭活出生后小鼠肾脏中的Kif3a。在新生小鼠中，Kif3a的肾特异性失活导致原发性纤毛的丢失，并主要在Henle环中产生肾囊肿，而在成年小鼠中，尽管原发性纤毛的丢失，但失活不会导致囊肿的快速发展。囊肿的年龄依赖性和位置表明，囊肿的形成需要增加细胞增殖的速度。为了验证这种可能性，我们通过诱导急性肾损伤和肾小管再生来刺激成人肾脏中的细胞增殖。急性肾损伤诱导成年Kif3a突变小鼠囊肿形成。对Kif3a突变小鼠囊前小管的分析表明，纤毛的缺失并没有刺激细胞增殖，而是导致细胞平面极性异常，表现为细胞分裂方向的异常。我们得出结论，初级纤毛是维持哺乳动物肾脏平面细胞极性所必需的，急性肾损伤会加剧囊性疾病。
Polycystic kidney disease (PKD) is an inherited disorder that is characterized by the accumulation of cysts in the renal parenchyma and progressive decline in renal function. Recent studies suggest that PKD arises from abnormalities of the primary cilium. We have previously shown that kidney-specific inactivation of the ciliogenic gene Kif3a during embryonic development produces kidney cysts and renal failure. Here, we used tamoxifen-inducible, kidney-specific gene targeting to inactivate Kif3a in the postnatal mouse kidney. Kidney-specific inactivation of Kif3a in newborn mice resulted in the loss of primary cilia and produced kidney cysts primarily in the loops of Henle, whereas inactivation in adult mice did not lead to the rapid development of cysts despite a comparable loss of primary cilia. The age-dependence and locations of the cysts suggested that cyst formation required increased rates of cell proliferation. To test this possibility, we stimulated cell proliferation in the adult kidney by inducing acute kidney injury and tubular regeneration. Acute kidney injury induced cyst formation in adult Kif3a mutant mice. Analysis of pre-cystic tubules in Kif3a mutant mice showed that the loss of cilia did not stimulate cell proliferation but instead resulted in aberrant planar cell polarity as manifested by abnormalities in the orientation of cell division. We conclude that primary cilia are required for the maintenance of planar cell polarity in the mammalian kidney and that acute kidney injury exacerbates cystic disease.