Protection of the transplant kidney during cold perfusion with doxycycline: proteomic analysis in a rat model

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Abstract

Background

It has been previously shown that doxycycline (Doxy) protects the kidney from preservation injury by inhibition of matrix metalloproteinase. However, the precise molecular mechanism involved in this protection from injury is not known. We used a pharmaco-proteomics approach to identify potential molecular targets associated with kidney preservation injury.

Methods

Rat kidneys were cold perfused with or without doxycycline (Doxy) for 22 h. Kidneys perfusates were analyzed for the presence of injury markers such as lactate dehydrogenase (LDH), and neutrophil-gelatinase associated lipocalin (NGAL). Proteins extracted from kidney tissue were analyzed by 2-dimensional gel electrophoresis. Proteins of interest were identified by mass spectrometry.

Results

Triosephosphate isomerase, PGM, dihydropteridine reductase-2, pyridine nucleotide-disulfide oxidoreductase, phosphotriesterase-related protein, and aminoacylase-1A were not affected by cold perfusion. Perfusion with Doxy increased their levels. N(G),N(G)-dimethylarginine dimethylaminohydrolase and phosphoglycerate kinase 1 were decreased after cold perfusion. Perfusion with Doxy led to an increase in their levels.

Conclusions

This study revealed specific metabolic enzymes involved in preservation injury and in the mechanism whereby Doxy protects the kidney against injury during cold perfusion.

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Most cited references 31

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Fast and Accurate Protein False Discovery Rates on Large-Scale Proteomics Data Sets with Percolator 3.0

Matthew The, Michael MacCoss, William Noble … (2016)

Percolator is a widely used software tool that increases yield in shotgun proteomics experiments and assigns reliable statistical confidence measures, such as q values and posterior error probabilities, to peptides and peptide-spectrum matches (PSMs) from such experiments. Percolator’s processing speed has been sufficient for typical data sets consisting of hundreds of thousands of PSMs. With our new scalable approach, we can now also analyze millions of PSMs in a matter of minutes on a commodity computer. Furthermore, with the increasing awareness for the need for reliable statistics on the protein level, we compared several easy-to-understand protein inference methods and implemented the best-performing method—grouping proteins by their corresponding sets of theoretical peptides and then considering only the best-scoring peptide for each protein—in the Percolator package. We used Percolator 3.0 to analyze the data from a recent study of the draft human proteome containing 25 million spectra (PM:24870542). The source code and Ubuntu, Windows, MacOS, and Fedora binary packages are available from http://percolator.ms/ under an Apache 2.0 license. Graphical Abstract ᅟ

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Doxycycline Alters Metabolism and Proliferation of Human Cell Lines

Ethan Ahler, William Sullivan Jr, Ashley Cass … (2013)

The tetracycline antibiotics are widely used in biomedical research as mediators of inducible gene expression systems. Despite many known effects of tetracyclines on mammalian cells–including inhibition of the mitochondrial ribosome–there have been few reports on potential off-target effects at concentrations commonly used in inducible systems. Here, we report that in human cell lines, commonly used concentrations of doxycycline change gene expression patterns and concomitantly shift metabolism towards a more glycolytic phenotype, evidenced by increased lactate secretion and reduced oxygen consumption. We also show that these concentrations are sufficient to slow proliferation. These findings suggest that researchers using doxycycline in inducible expression systems should design appropriate controls to account for potential confounding effects of the drug on cellular metabolism.

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New intracellular activities of matrix metalloproteinases shine in the moonlight.

Parker Jobin, Georgina Butler, Christopher Overall (2017)

Adaption of a single protein to perform multiple independent functions facilitates functional plasticity of the proteome allowing a limited number of protein-coding genes to perform a multitude of cellular processes. Multifunctionality is achievable by post-translational modifications and by modulating subcellular localization. Matrix metalloproteinases (MMPs), classically viewed as degraders of the extracellular matrix (ECM) responsible for matrix protein turnover, are more recently recognized as regulators of a range of extracellular bioactive molecules including chemokines, cytokines, and their binders. However, growing evidence has convincingly identified select MMPs in intracellular compartments with unexpected physiological and pathological roles. Intracellular MMPs have both proteolytic and non-proteolytic functions, including signal transduction and transcription factor activity thereby challenging their traditional designation as extracellular proteases. This review highlights current knowledge of subcellular location and activity of these "moonlighting" MMPs. Intracellular roles herald a new era of MMP research, rejuvenating interest in targeting these proteases in therapeutic strategies. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.

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Author and article information

Contributors

Michael A. J. Moser: mike.moser@usask.ca

Grzegorz Sawicki: greg.sawicki@usask.ca

Journal

Journal ID (nlm-ta): Proteome Sci

Journal ID (iso-abbrev): Proteome Sci

Title: Proteome Science

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-5956

Publication date (Electronic): 20 April 2020

Publication date PMC-release: 20 April 2020

Publication date Collection: 2020

Volume: 18

Electronic Location Identifier: 3

Affiliations

[1 ]GRID grid.25152.31, ISNI 0000 0001 2154 235X, Department of Surgery, , University of Saskatchewan, ; Saskatoon, Saskatchewan Canada

[2 ]GRID grid.25152.31, ISNI 0000 0001 2154 235X, Department of Anatomy, Physiology and Pharmacology, , University of Saskatchewan, ; Saskatoon, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5 Canada

[3 ]GRID grid.4495.c, ISNI 0000 0001 1090 049X, Department of Medical Laboratory Diagnostics, Division of Clinical Chemistry, , Wroclaw Medical University, ; Wroclaw, Poland

[4 ]GRID grid.55602.34, ISNI 0000 0004 1936 8200, Proteomics and Mass Spectrometry Core Facility. Life Sciences Research Institute, , Dalhousie University, ; Halifax, Nova Scotia Canada

Article

Publisher ID: 159

DOI: 10.1186/s12953-020-00159-3

PMC ID: 7171734

SO-VID: 7bf5f2b0-3ed8-4f50-8546-71e06414df85

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 5 January 2020

Date accepted : 31 March 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004281, Narodowe Centrum Nauki;

Award ID: UMO-2017/27/B/NZ4/00601

Award Recipient : Grzegorz Sawicki

Custom metadata

ScienceOpen disciplines: Molecular biology

Keywords: cold perfusion,doxycycline,kidney proteome,kidney transplantation,pharmacological protection

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ScienceOpen disciplines: Molecular biology

Keywords: cold perfusion, doxycycline, kidney proteome, kidney transplantation, pharmacological protection

Protection of the transplant kidney during cold perfusion with doxycycline: proteomic analysis in a rat model

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Abstract

Background

Methods

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Conclusions

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Higher order chromatin architecture

Most cited references 31

Fast and Accurate Protein False Discovery Rates on Large-Scale Proteomics Data Sets with Percolator 3.0

Doxycycline Alters Metabolism and Proliferation of Human Cell Lines

New intracellular activities of matrix metalloproteinases shine in the moonlight.

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