The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury
Authors: Johnsen Marc , Kubacki Torsten , Yeroslaviz Assa , Späth Martin Richard , Mörsdorf Jannis , Göbel Heike , Bohl Katrin , Ignarski Michael , Meharg Caroline , Habermann Bianca , Altmüller Janine , Beyer Andreas , Benzing Thomas , Schermer Bernhard , Burst Volker , Müller Roman-Ulrich 
Published: February 2020

Significance Statement
Preconditioning strategies, such as caloric restriction and hypoxic preconditioning, show strongly protective effects in animal models of AKI, and researchers hope exploration of these strategies might provide insights into translating these powerful interventions to the clinical setting. However, the molecular mechanisms underlying the beneficial effects of short-term application of caloric restriction and hypoxic preconditioning have remained elusive. The authors used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning before and after renal ischemia-reperfusion injury, identifying genes and pathways commonly shared by the two strategies. A comparison of these findings with genes dysregulated during AKI points to genes involved in preconditioning-associated organ protection that can now be examined as potential therapeutic targets in AKI.

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/).