A Functional Landscape of CKD Entities From Public Transcriptomic Data

Ferenc Tajti; Christoph Kuppe; Asier Antoranz; Mahmoud M Ibrahim; Hyojin Kim; Francesco Ceccarelli; Christian H Holland; Hannes Olauson; Jürgen Floege; Leonidas G Alexopoulos; Rafael Kramann; Julio Saez-Rodriguez

doi:10.1016/j.ekir.2019.11.005

A Functional Landscape of CKD Entities From Public Transcriptomic Data

Kidney Int Rep. 2019 Nov 13;5(2):211-224. doi: 10.1016/j.ekir.2019.11.005. eCollection 2020 Feb.

Authors

Ferenc Tajti^{1

2}, Christoph Kuppe², Asier Antoranz^{3

4}, Mahmoud M Ibrahim^{1

2}, Hyojin Kim¹, Francesco Ceccarelli¹, Christian H Holland^{1

5}, Hannes Olauson⁶, Jürgen Floege², Leonidas G Alexopoulos^{3

4}, Rafael Kramann², Julio Saez-Rodriguez^{1

5}

Affiliations

¹ Faculty of Medicine, RWTH Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany.
² Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
³ Department of Mechanical Engineering, National Technical University of Athens, Athens, Greece.
⁴ Department of Testing Services, ProtATonce Ltd., Athens, Greece.
⁵ Institute for Computational Biomedicine, Heidelberg University, Bioquant, Heidelberg, Germany.
⁶ Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

Abstract

Introduction: To develop effective therapies and identify novel early biomarkers for chronic kidney disease, an understanding of the molecular mechanisms orchestrating it is essential. We here set out to understand how differences in chronic kidney disease (CKD) origin are reflected in gene expression. To this end, we integrated publicly available human glomerular microarray gene expression data for 9 kidney disease entities that account for most of CKD worldwide. Our primary goal was to demonstrate the possibilities and potential on data analysis and integration to the nephrology community.

Methods: We integrated data from 5 publicly available studies and compared glomerular gene expression profiles of disease with that of controls from nontumor parts of kidney cancer nephrectomy tissues. A major challenge was the integration of the data from different sources, platforms, and conditions that we mitigated with a bespoke stringent procedure.

Results: We performed a global transcriptome-based delineation of different kidney disease entities, obtaining a transcriptomic diffusion map of their similarities and differences based on the genes that acquire a consistent differential expression between each kidney disease entity and nephrectomy tissue. We derived functional insights by inferring the activity of signaling pathways and transcription factors from the collected gene expression data and identified potential drug candidates based on expression signature matching. We validated representative findings by immunostaining in human kidney biopsies indicating, for example, that the transcription factor FOXM1 is significantly and specifically expressed in parietal epithelial cells in rapidly progressive glomerulonephritis (RPGN) whereas not expressed in control kidney tissue. Furthermore, we found drug candidates by matching the signature on expression of drugs to that of the CKD entities, in particular, the Food and Drug Administration-approved drug nilotinib.

Conclusion: These results provide a foundation to comprehend the specific molecular mechanisms underlying different kidney disease entities that can pave the way to identify biomarkers and potential therapeutic targets. To facilitate further use, we provide our results as a free interactive Web application: https://saezlab.shinyapps.io/ckd_landscape/. However, because of the limitations of the data and the difficulties in its integration, any specific result should be considered with caution. Indeed, we consider this study rather an illustration of the value of functional genomics and integration of existing data.

Keywords: CKD; drug repositioning; signaling pathway; transcription factor.