Pathophysiology of ARPKD: role of aberrant transport

多囊肾病（PKD）的遗传形式包括常见的常染色体显性形式（ADPKD），大约1000人中有1人患病，以及不太常见的常染色体隐性形式（ARPKD），大约20000例活产婴儿中有1人患病。这两种疾病的特点都是源自肾元特定部分的囊肿的形成和扩大。在ADPKD中，正常肾实质逐渐被多个肾单元段产生的囊肿破坏，导致大约50%的患者在60岁时肾功能衰竭。ARPKD是一种婴儿发病率高的疾病，其特征是集束管进行性扩张，集束管是肾元段，负责最终调节肾内钠、钾、酸碱和水的平衡。在囊肿的形成和扩张过程中涉及三种机制：细胞增殖、异常的细胞外基质和粘附、净上皮液。虽然已有数据表明前两个过程与ARPKD的发病机制有关，但对该疾病中经上皮溶质和水转运的调节知之甚少。我们的长期目标是确定上皮细胞运输途径的表达和调节的改变，这些改变不仅有助于囊肿扩张，而且还有助于APRKD中高血压和多尿的早期发病。在这项为期5年的研究中，我们提出的假设主要集中在(1)表征离子通道、转运体和受体的分子和功能表达，以及（2、3）探索异常的自分泌/旁分泌信号和/或细胞对生物力学力的反应导致ARPKD收集性粉尘囊中上皮转运失调的机制。为了更好地了解人类疾病的发病机制，我们建议在来自人类ARPKD收集管囊肿或年龄匹配的正常人类肾脏（NHK）的永生化主要细胞系中进行本应用中描述的大多数研究。平行研究也将在ARPKD的orpk小鼠模型中进行，其微解剖小管可以在体外分离和微灌注。

The hereditary forms of polycystic kidney disease (PKD) include the common autosomal dominant form (ADPKD), affecting 1 in approximately 1000 of the population, and the less common autosomal recessive form (ARPKD), affecting 1 in approximately 20,000 live births. Both diseases are characterized by the formation and expansion of cysts derived from specific segments of the nephron. In ADPKD, the gradual destruction of normal renal parenchyma by cysts arising in multiple nephron segments lead to renal failure in approximately 50% of patients by the sixth decade of life. ARPKD, a disease with high infant morbidity, is characterized by the progressive dilatation of collecting ducts, the nephron segment responsible for the final renal regulation of Na, K, acid-base and water balance. Three mechanisms have been implicated in the process of cyst formation and expansion: cell proliferation, abnormal extracellular matrix and adhesion, and net transepithelial fluid. Whereas data exists to implicate the former two processes in the pathogenesis of ARPKD, little is known about the regulation of transepithelial solute and water transport in this disease. Our long term goal is to identify alterations in the expression and regulation of epithelial cell transport pathways that contribute not only to cyst expansion, but also the early onset of hypertension and polyuria in APRKD. The hypotheses we propose to examine in this 5-year application are focused on (I) characterizing the molecular and functional expression of ion channels, transporters, and receptors, and (II, III) exploring the mechanisms by which aberrant autocrine/paracrine signaling and/or cellular responses to biomechanical forces lead to dysregulated transepithelial transport in ARPKD collecting dust cysts. To best understand the pathogenesis of human disease, we propose to perform most studies described in this application in immortalized principal cell lines derived from human ARPKD collecting duct cysts or age-matched normal human kidney (NHK). Parallel studies will also be performed in the orpk murine model of ARPKD, whose microdissected tubules can be isolated and microperfused in vitro.