Marc Johnsen1, Torsten Kubacki1, Assa Yeroslaviz2, Martin Richard Späth1, Jannis Mörsdorf1, Heike Göbel3, Katrin Bohl1,4, Michael Ignarski1,4, Caroline Meharg5, Bianca Habermann6, Janine Altmüller7, Andreas Beyer3,8, Thomas Benzing1,3,8, Bernhard Schermer1,3,8, Volker Burst9, Roman-Ulrich Müller9,3,8. 1. Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. 2. Max Planck Institute of Biochemistry, Martinsried, Germany. 3. Institute for Pathology, Diagnostic and Experimental Nephropathology Unit. 4. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases. 5. Institute for Global Food Security, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom; and. 6. Development Biology Institute of Marseille, Aix-Marseille University, CNRS, Marseille, France. 7. Cologne Center for Genomics, and. 8. Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. 9. Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; roman-ulrich.mueller@uk-koeln.de volker.burst@uk-koeln.de.
Abstract
BACKGROUND: Although AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance. METHODS: To identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury. RESULTS: The gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI. CONCLUSIONS: This comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).
BACKGROUND: Although AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance. METHODS: To identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury. RESULTS: The gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI. CONCLUSIONS: This comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).
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