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  • Ovid Technologies (Wolters Kluwer Health)  (3)
  • Ignarski, Michael  (3)
  • 1
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    Online Resource
    The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Journal of the American Society of Nephrology Vol. 31, No. 4 ( 2020-4), p. 716-730
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 4 ( 2020-4), p. 716-730
    Abstract: 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/).
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2019050534
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2029124-3
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  • 2
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    Online Resource
    Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology Vol. 34, No. 5 ( 2023-05), p. 772-792
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 5 ( 2023-05), p. 772-792
    Abstract: AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. Background Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. Methods Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. Results We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. Conclusions CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.0000000000000087
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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  • 3
    Online Resource
    Online Resource
    The RNA-Protein Interactome of Differentiated Kidney Tubular Epithelial Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Journal of the American Society of Nephrology Vol. 30, No. 4 ( 2019-4), p. 564-576
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 4 ( 2019-4), p. 564-576
    Abstract: RNA-binding proteins (RBPs) are crucial regulators of cellular biology, and recent evidence suggests that regulation of RBPs that modulate both RNA stability and translation may have a profound effect on the proteome. However, little is known about regulation of RBPs upon clinically relevant changes of the cellular microenvironment. The authors used high-throughput approaches to study the cellular RNA‐binding proteome in differentiated tubular epithelial cells exposed to hypoxia. They identified a number of novel RBPs (suggesting that these proteins may be specific RBPs in differentiated tubular epithelial cells), and found quantitative differences in RBP-binding to mRNA associated with hypoxia versus normoxia. These findings demonstrate the regulation of RBPs through environmental stimuli and provide insight into the biology of hypoxia-response signaling in the kidney. Background RNA-binding proteins (RBPs) are fundamental regulators of cellular biology that affect all steps in the generation and processing of RNA molecules. Recent evidence suggests that regulation of RBPs that modulate both RNA stability and translation may have a profound effect on the proteome. However, regulation of RBPs in clinically relevant experimental conditions has not been studied systematically. Methods We used RNA interactome capture, a method for the global identification of RBPs to characterize the global RNA‐binding proteome (RBPome) associated with polyA-tailed RNA species in murine ciliated epithelial cells of the inner medullary collecting duct. To study regulation of RBPs in a clinically relevant condition, we analyzed hypoxia-associated changes of the RBPome. Results We identified 〉 1000 RBPs that had been previously found using other systems. In addition, we found a number of novel RBPs not identified by previous screens using mouse or human cells, suggesting that these proteins may be specific RBPs in differentiated kidney epithelial cells. We also found quantitative differences in RBP-binding to mRNA that were associated with hypoxia versus normoxia. Conclusions These findings demonstrate the regulation of RBPs through environmental stimuli and provide insight into the biology of hypoxia-response signaling in epithelial cells in the kidney. A repository of the RBPome and proteome in kidney tubular epithelial cells, derived from our findings, is freely accessible online, and may contribute to a better understanding of the role of RNA-protein interactions in kidney tubular epithelial cells, including the response of these cells to hypoxia.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2018090914
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2029124-3
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