Molecular pathogenesis of autosomal dominant polycystic kidney disease
Molecular pathogenesis of autosomal dominant polycystic kidney disease
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DOI：
10.1017/s1462399406010362
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发表时间：
2006-01-17
影响因子：
6.2
通讯作者：
Sandford, Richard
中科院分区：
文献类型：
--
作者：
Yoder, Bradley K.;Mulroy, Sharon;Sandford, Richard
常染色体显性遗传性多囊肾病（ADPKD）是最常见的人类遗传性疾病之一，但仍相对未知的更广泛的医疗，科学和公众观众。ADPKD的特征是双侧肾脏增大，其中包含多个充满液体的囊肿，并且是终末期肾衰竭（ESRF）的主要原因。ADPKD是由两个基因突变引起的：PKD 1和PKD 2。PKD基因的蛋白质产物多囊蛋白-1和多囊蛋白-2形成钙调节的、钙可渗透的离子通道。多囊蛋白复合物通过多种信号转导途径参与细胞周期的调节以及肾初级纤毛的机械感觉功能，这是一种神秘的细胞器，其在正常生理学中的作用仍然知之甚少。纤毛功能的缺陷，现在记录在几个其他人类疾病，包括常染色体隐性遗传性多囊肾病，肾单位营养不良，Bardet-Biedl综合征和多囊肾病的许多动物模型。在这些多囊肾疾病动物模型中进行的治疗试验已经确定了几种有前途的药物，可以改善疾病的严重程度。然而，阐明多囊蛋白和初级纤毛的功能将对我们对肾囊肿疾病的理解产生重大影响，并将为疾病特异性治疗的设计创造令人兴奋的新机会。
Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest inherited human disorders yet remains relatively unknown to the wider medical, scientific and public audience. ADPKD is characterised by the development of bilateral enlarged kidneys containing multiple fluid-filled cysts and is a leading cause of end-stage renal failure (ESRF). ADPKD is caused by mutations in two genes: PKD1 and PKD2. The protein products of the PKDgenes, polycystin-1 and polycystin-2, form a calcium-regulated, calcium-permeable ion channel. The polycystin complex is implicated in regulation of the cell cycle via multiple signal transduction pathways as well as the mechanosensory function of the renal primary cilium, an enigmatic cellular organelle whose role in normal physiology is still poorly understood. Defects in cilial function are now documented in several other human diseases including autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome and many animal models of polycystic kidney disease. Therapeutic trials in these animal models of polycystic kidney disease have identified several promising drugs that ameliorate disease severity. However, elucidation of the function of the polycystins and the primary cilium will have a major impact on our understanding of renal cystic diseases and will create exciting new opportunities for the design of disease-specific therapies.