Profiling conserved biological pathways in Autosomal Dominant Polycystic Kidney Disorder (ADPKD) to elucidate key transcriptomic alterations regulating cystogenesis: A cross-species meta-analysis approach
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Published on: June 23, 2015
Shatakshee Chatterjee1, Srikant Prasad Verma1, Priyanka Pandey1
1National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (T.B. Hospital), 2nd Floor, P.O.: N.S.S., Kalyani 741251, West-Bengal, India.
Purpose:
Initiation and progression of fluid filled cysts mark Autosomal Dominant Polycystic Kidney Disease (ADPKD). Thus, improved therapeutics targeting cystogenesis remains a constant challenge. Microarray studies in single ADPKD animal models species with limited sample sizes tend to provide scattered views on underlying ADPKD pathogenesis. Thus we aim to perform a cross species meta-analysis to profile conserved biological pathways that might be key targets for therapy.
Methods:
Nine ADPKD microarray datasets on rat, mice and human fulfilled our study criteria and were chosen. Intra-species combined analysis was performed after considering removal of batch effect. Significantly enriched GO biological processes and KEGG pathways were computed and their overlap was observed. For the conserved pathways, biological modules and gene regulatory networks were observed. Additionally, Gene Set Enrichment Analysis (GSEA) using Molecular Signature Database (MSigDB) was performed for genes found in conserved pathways.
Results:
We obtained 28 modules of significantly enriched GO processes and 5 major functional categories from significantly enriched KEGG pathways conserved in human, mice and rats that in turn suggest a global transcriptomic perturbation affecting cyst - formation, growth and progression. Significantly enriched pathways obtained from up-regulated genes such as Genomic instability, Protein localization in ER and Insulin Resistance were found to regulate cyst formation and growth whereas cyst progression due to increased cell adhesion and inflammation was suggested by perturbations in Angiogenesis, TGF-beta, CAMs, and Infection related pathways. Additionally, networks revealed shared genes among pathways e.g. SMAD2 and SMAD7 in Endocytosis and TGF-beta.
Conclusion:
Our study suggests cyst formation and progression to be an outcome of interplay between a set of several key deregulated pathways. Thus, further translational research is warranted focusing on developing a combinatorial therapeutic approach for ADPKD redressal.
Insights
This study analyzed multiple Autosomal Dominant Polycystic Kidney Disease (ADPKD) datasets to identify conserved pathways involved in cyst formation. Findings reveal key deregulated pathways offering potential targets for new combinatorial therapies for ADPKD.
Area of Science:
- Genomics and Bioinformatics
- Translational Medicine
- Molecular Biology
Background:
- Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by fluid-filled cysts, and effective therapeutics targeting cystogenesis are challenging to develop.
- Existing microarray studies in ADPKD animal models are limited by sample size and species specificity, providing fragmented insights into pathogenesis.
Purpose of the Study:
- To conduct a cross-species meta-analysis of ADPKD microarray data to identify conserved biological pathways.
- To uncover potential therapeutic targets for ADPKD by profiling shared molecular mechanisms across species.
Main Methods:
- Meta-analysis of nine ADPKD microarray datasets from human, mouse, and rat models.
- Identification of significantly enriched Gene Ontology (GO) biological processes and KEGG pathways, with analysis of conserved pathways and gene regulatory networks.
- Gene Set Enrichment Analysis (GSEA) using the Molecular Signature Database (MSigDB) for genes within conserved pathways.
Main Results:
- Identification of 28 conserved GO modules and 5 KEGG pathway categories indicating global transcriptomic perturbations in cyst formation, growth, and progression.
- Key pathways regulating cyst formation and growth include Genomic instability, ER protein localization, and Insulin Resistance.
- Cyst progression is linked to increased cell adhesion and inflammation via Angiogenesis, TGF-beta, CAMs, and Infection-related pathways, with shared genes like SMAD2 and SMAD7 observed.
Conclusions:
- ADPKD cyst formation and progression result from the complex interplay of multiple deregulated pathways.
- Translational research focusing on combinatorial therapeutic strategies is essential for effective ADPKD treatment.
