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NS398 as a potential drug for autosomal-dominant polycystic kidney disease: Analysis using bioinformatics,and zebrafish and mouse models |
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| Authors: | Sixiu Chen Linxi Huang Shoulian Zhou Qingzhou Zhang Mengna Ruan Lili Fu Bo Yang Dechao Xu Changlin Mei Zhiguo Mao |
| Affiliation: | 1. Division of Nephrology, Kidney Institute of People’s Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China;2. Division of Nephrology, Kidney Institute of People’s Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China Graduate School of Clinical Medicine, Second Military Medical University, Shanghai, China Contribution: Data curation (equal), Formal analysis (equal), Investigation (equal), Methodology (equal), Software (equal), Validation (equal), Visualization (lead), Writing - original draft (equal);3. Division of Nephrology, Kidney Institute of People’s Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China Graduate School of Clinical Medicine, Second Military Medical University, Shanghai, China Contribution: Data curation (equal), Formal analysis (equal), Investigation (equal), Methodology (equal), Validation (lead), Writing - original draft (equal);4. Division of Nephrology, Kidney Institute of People’s Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China Contribution: Data curation (equal), Formal analysis (equal), Software (lead);5. Division of Nephrology, Kidney Institute of People’s Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China Contribution: Formal analysis (equal), Investigation (equal), Methodology (equal), Validation (equal);6. Division of Nephrology, Kidney Institute of People’s Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China Contribution: Data curation (equal), Formal analysis (equal), Visualization (equal);7. Internal Medicine Ⅲ (Nephrology and Endocrinology), Naval Medical Center of PLA, Second Military Medical University, Shanghai, China Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal);8. Division of Nephrology, Kidney Institute of People’s Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Resources (supporting), Writing - original draft (supporting) |
| Abstract: | 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. |
| Keywords: | autosomal-dominant polycystic kidney disease bioinformatics analysis clear-cell renal cell carcinoma cystogenesis NS398 |