Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by uncontrolled renal cyst formation, and few treatment options are available. There are many parallels between ADPKD and clear-cell renal cell carcinoma (ccRCC); however, few studies have addressed the mechanisms linking them. In this study, we aimed to investigate their convergences and divergences based on bioinformatics and explore the potential of compounds commonly used in cancer research to be repurposed for ADPKD. We analysed gene expression datasets of ADPKD and ccRCC to identify the common and disease-specific differentially expressed genes (DEGs). We then mapped them to the Connectivity Map database to identify small molecular compounds with therapeutic potential. A total of 117 significant DEGs were identified, and enrichment analyses results revealed that they are mainly enriched in arachidonic acid metabolism, p53 signalling pathway and metabolic pathways. In addition, 127 ccRCC-specific up-regulated genes were identified as related to the survival of patients with cancer. We focused on the compound NS398 as it targeted DEGs and found that it inhibited the proliferation of Pkd1^−/− and 786-0 cells. Furthermore, its administration curbed cystogenesis in Pkd2 zebrafish and early-onset Pkd1-deficient mouse models. In conclusion, NS398 is a potential therapeutic agent for ADPKD.

中文翻译：

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NS398 作为常染色体显性多囊肾病的潜在药物：使用生物信息学、斑马鱼和小鼠模型进行分析

常染色体显性遗传多囊肾病 (ADPKD) 的特点是肾囊肿形成不受控制，可用的治疗选择很少。ADPKD 与透明细胞肾细胞癌 (ccRCC) 之间有许多相似之处；然而，很少有研究涉及将它们联系起来的机制。在这项研究中，我们旨在基于生物信息学研究它们的收敛和分歧，并探索癌症研究中常用的化合物重新用于 ADPKD 的潜力。我们分析了 ADPKD 和 ccRCC 的基因表达数据集，以确定常见和疾病特异性差异表达基因 (DEG)。然后，我们将它们映射到 Connectivity Map 数据库，以识别具有治疗潜力的小分子化合物。共确定了 117 个重要的 DEG，富集分析结果显示，它们主要富集于花生四烯酸代谢、p53信号通路和代谢通路。此外，127 个 ccRCC 特异性上调基因被确定为与癌症患者的生存相关。我们专注于化合物 NS398，因为它靶向 DEG，发现它抑制了Pkd1 ^-/-和 786-0 细胞。此外，它的给药抑制了Pkd2斑马鱼和早发性Pkd1 缺陷小鼠模型中的囊肿形成。总之，NS398 是 ADPKD 的潜在治疗剂。