Development of polycystic kidney disease in juvenile cystic kidney mice: Insights into pathogenesis, ciliary abnormalities, and common features with human disease
Development of polycystic kidney disease in juvenile cystic kidney mice: Insights into pathogenesis, ciliary abnormalities, and common features with human disease
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DOI：
10.1681/asn.2006020136
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发表时间：
2006-10-01
影响因子：
13.6
通讯作者：
Ibraghimov-Beskrovnaya, Oxana
中科院分区：
文献类型：
--
作者：
Smith, Laurie A.;Bukanov, Nikolay O.;Ibraghimov-Beskrovnaya, Oxana
近年来，对多囊肾病(PKD)分子机制的研究取得了显著进展。将这一理解转化为有效的疗法将需要在动物模型中进行测试，这些动物模型在多个参数上与人类PKD非常相似。与常染色体显性遗传性PKD相似，幼年囊性肾(JCK)小鼠可在多个肾单位段形成囊肿，包括皮质集合管、远端小管和Henle环。在肾脏疾病的进展中，JCK小鼠表现出性别二型性，而雄性小鼠的疾病更具侵袭性。性腺切除实验表明，睾酮会加重JCK雄性小鼠的疾病严重程度，而雌性性腺激素具有保护作用。EGF受体在人类疾病的标志--JCK囊性上皮中过度表达和定位错误。JCK肾脏中cAMP水平的增加和B-Raf/细胞外信号调节激酶途径的激活被证实。首次发现JCK突变对NIMA相关(从不在有丝分裂A中)激酶NEK8和多囊蛋白在JCK纤毛中表达的影响。在JCK上皮中NEK8的过度表达和纤毛定位的丧失伴随着沿纤毛的多囊蛋白表达的增强。JCK肾脏的初级纤毛明显长于野生型小鼠的纤毛，提示NEK8在控制纤毛长度方面起作用。总而言之，这些数据表明，JCK小鼠应该有助于测试潜在的治疗方法，并研究将睫毛结构/功能和囊变联系起来的分子机制。
Significant progress in understanding the molecular mechanisms of polycystic kidney disease (PKD) has been made in recent years. Translating this understanding into effective therapeutics will require testing in animal models that closely resemble human PKD by multiple parameters. Similar to autosomal dominant PKD, juvenile cystic kidney (jck) mice develop cysts in multiple nephron segments, including cortical collecting ducts, distal tubules, and loop of Henle. The jck mice display gender dimorphism in kidney disease progression with more aggressive disease in male mice. Gonadectomy experiments show that testosterone aggravates the severity of the disease in jck male mice, while female gonadal hormones have protective effects. EGF receptor is overexpressed and mislocalized in jck cystic epithelia, a hallmark of human disease. Increased cAMP levels in jck kidneys and activation of the B-Raf/extracellular signal-regulated kinase pathway are demonstrated. The effect of jck mutation on the expression of Nek8, a NIMA-related (never in mitosis A) kinase, and polycystins in jck cilia is shown for the first time. Nek8 overexpression and loss of ciliary localization in jck epithelia are accompanied by enhanced expression of polycystins along the cilia. The primary cilia in jck kidneys are significantly more lengthened than the cilia in wild-type mice, suggesting a role for Nek8 in controlling ciliary length. Collectively, these data demonstrate that the jck mice should be useful for testing potential therapies and for studying the molecular mechanisms that link ciliary structure/f unction and cystogenesis.