Menezes L F, Onuchic L F
Disciplina de Nefrologia, Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo 455, Sala 3310, 01246-903 São Paulo, SP, Brazil.
Braz J Med Biol Res. 2006 Dec;39(12):1537-48. doi: 10.1590/s0100-879x2006001200004.
Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disease characterized by a malformation complex which includes cystically dilated tubules in the kidneys and ductal plate malformation in the liver. The disorder is observed primarily in infancy and childhood, being responsible for significant pediatric morbidity and mortality. All typical forms of ARPKD are caused by mutations in a single gene, PKHD1 (polycystic kidney and hepatic disease 1). This gene has a minimum of 86 exons, assembled into multiple differentially spliced transcripts and has its highest level of expression in kidney, pancreas and liver. Mutational analyses revealed that all patients with both mutations associated with truncation of the longest open reading frame-encoded protein displayed the severe phenotype. This product, polyductin, is a 4,074-amino acid protein expressed in the cytoplasm, plasma membrane and primary apical cilia, a structure that has been implicated in the pathogenesis of different polycystic kidney diseases. In fact, cholangiocytes isolated from an ARPKD rat model develop shorter and dysmorphic cilia, suggesting polyductin to be important for normal ciliary morphology. Polyductin seems also to participate in tubule morphogenesis and cell mitotic orientation along the tubular axis. The recent advances in the understanding of in vitro and animal models of polycystic kidney diseases have shed light on the molecular and cellular mechanisms of cyst formation and progression, allowing the initiation of therapeutic strategy designing and promising perspectives for ARPKD patients. It is notable that vasopressin V2 receptor antagonists can inhibit/halt the renal cystic disease progression in an orthologous rat model of human ARPKD.
常染色体隐性多囊肾病（ARPKD）是一种遗传性疾病，其特征为一种畸形综合征，包括肾脏中呈囊状扩张的肾小管以及肝脏中的导管板畸形。该疾病主要在婴儿期和儿童期出现，是儿童发病和死亡的重要原因。所有典型形式的ARPKD均由单个基因PKHD1（多囊肾和肝病1）的突变引起。该基因至少有86个外显子，组装成多个差异剪接的转录本，在肾脏、胰腺和肝脏中表达水平最高。突变分析显示，所有具有与最长开放阅读框编码蛋白截断相关的两种突变的患者均表现出严重的表型。这种产物，即多囊蛋白，是一种由4074个氨基酸组成的蛋白质，在细胞质、质膜和初级顶纤毛中表达，而初级顶纤毛这种结构与不同多囊肾病的发病机制有关。事实上，从ARPKD大鼠模型中分离出的胆管细胞会发育出更短且形态异常的纤毛，这表明多囊蛋白对正常纤毛形态很重要。多囊蛋白似乎也参与肾小管形态发生以及细胞沿肾小管轴的有丝分裂方向。在多囊肾病体外和动物模型理解方面的最新进展，为囊肿形成和进展的分子及细胞机制提供了线索，从而开启了治疗策略设计，并为ARPKD患者带来了有前景的展望。值得注意的是，血管加压素V2受体拮抗剂可在人类ARPKD的同源大鼠模型中抑制/阻止肾囊性疾病的进展。
