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Published on: February 20, 2015
NS398 as a potential drug for autosomal-dominant polycystic kidney disease: Analysis using bioinformatics, and
Sixiu Chen1, Linxi Huang1,2, Shoulian Zhou1,2
1Division of Nephrology, Kidney Institute of People's Liberation Army (PLA), Changzheng Hospital, Second Military Medical University, Shanghai, China.
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.
Insights
Autosomal-dominant polycystic kidney disease (ADPKD) shows promise with repurposed cancer drugs. The compound NS398 effectively inhibited cyst formation in preclinical models, suggesting a new therapeutic avenue for ADPKD.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Autosomal-dominant polycystic kidney disease (ADPKD) is a genetic disorder causing kidney cysts with limited treatment options.
- Clear-cell renal cell carcinoma (ccRCC) shares biological similarities with ADPKD, yet the underlying mechanisms are not fully understood.
- Investigating shared pathways could reveal novel therapeutic strategies for ADPKD.
Purpose of the Study:
- To identify common and distinct molecular pathways between ADPKD and ccRCC using bioinformatics.
- To explore the repurposing of existing cancer drugs for ADPKD treatment.
- To evaluate the therapeutic potential of identified compounds in ADPKD models.
Main Methods:
- Analysis of gene expression datasets for ADPKD and ccRCC to find differentially expressed genes (DEGs).
- Utilizing the Connectivity Map database to identify potential therapeutic small molecules targeting DEGs.
- In vitro cell proliferation assays and in vivo studies using zebrafish and mouse models of ADPKD.
Main Results:
- Identified 117 significant DEGs common to ADPKD and ccRCC, enriched in arachidonic acid metabolism and p53 signaling pathways.
- Discovered 127 ccRCC-specific upregulated genes associated with patient survival.
- The compound NS398 inhibited proliferation in Pkd1-/- and 786-0 cells and reduced cystogenesis in Pkd2 zebrafish and Pkd1-deficient mice.
Conclusions:
- NS398 demonstrates therapeutic potential for ADPKD by targeting shared molecular pathways.
- Drug repurposing from cancer research offers a viable strategy for ADPKD treatment.
- Further investigation into NS398 could lead to a novel therapy for ADPKD.
