Cyst formation in the PKD2 (1-703) transgenic rat precedes deregulation of proliferation-related pathways

Polycystic Kidney Disease is characterized by the formation of large fluid-filled cysts that eventually destroy the renal parenchyma leading to end-stage renal failure. Although remarkable progress has been made in understanding the pathologic mechanism of the disease, the precise orchestration of the early events leading to cyst formation is still unclear. Abnormal cellular proliferation was traditionally considered to be one of the primary irregularities leading to cyst initiation and growth. Consequently, many therapeutic interventions have focused on targeting this abnormal proliferation, and some have even progressed to clinical trials. However, the role of proliferation in cyst development was primarily examined at stages where cysts are already visible in the kidneys and therefore at later stages of disease development. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters. Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0,6 and 24 days after birth) we performed gene expression profiling of kidney cells.

多囊肾病（Polycystic Kidney Disease, PKD）以大量充满液体的囊肿形成为特征，这些囊肿最终会破坏肾实质，进而引发终末期肾衰竭。尽管学界在阐明该病的病理机制方面已取得显著进展，但诱发囊肿形成的早期事件的精确调控程序仍未被完全揭示。传统观点认为，异常细胞增殖是引发囊肿起始与生长的核心异常之一。因此，诸多治疗干预手段均以靶向这种异常增殖为核心方向，部分研究甚至已推进至临床试验阶段。然而，此前关于增殖在囊肿发生发展中的作用的研究，主要集中在肾脏中已出现可见囊肿的疾病较晚期阶段。本研究聚焦于出生后即出现的囊性表型，旨在阐明细胞增殖在囊肿发生发展中的时序性贡献。我们使用不同日龄（出生后0~60天）的PKD2转基因大鼠模型（PKD2 (1-703)），开展了基因表达谱分析，并通过检测多项肾脏参数进行表型分析。表型分析结果显示，该PKD2转基因大鼠模型在出生后即刻便出现肾囊肿。另一方面，基因表达谱分析证实，异常增殖仅发生在疾病的较晚阶段。有趣的是，在该多囊肾病模型的疾病早期，其他通路已出现失调。我们的研究数据表明，囊肿形成先于增殖相关通路的失调，这提示增殖异常可能更多参与囊肿的生长过程，而非囊肿的起始形成。本研究再次聚焦于出生后即出现的囊性表型，旨在明确细胞增殖在囊肿发生发展中的时序性贡献。我们使用不同日龄（出生后0、6、24天）的PKD2转基因大鼠模型（PKD2 (1-703)），对肾脏细胞开展了基因表达谱分析。