A Functional Landscape of CKD Entities From Public Transcriptomic Data

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.

Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis

“…ª 2020 The Authors EMBO Molecular Medicine 12: e11021 | 2020 activities were downregulated ( Fig 8B). Comparison to the results generated from public microarray data sets of CKD patients (Tajti et al, 2019) showed that 9 out of 11 pathways (82%) were similarly regulated in our mice compared to patients. We next generated regulatory causal networks from both murine and human data sets with the tool CARNIVAL (Liu et al, 2019).…”

Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease

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SARS-CoV-2 infection risk assessment in the endometrium: viral infection-related gene expression across the menstrual cycle

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