El-Rashid, M; Nguyen-Ngo, D; Minhas, N; Meijles, DN; Li, J; Ghimire, K; Julovi, S; Rogers, NM
(2020)
Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury.
Sci Rep, 10 (1).
p. 21968.
ISSN 2045-2322
https://doi.org/10.1038/s41598-020-78936-5
SGUL Authors: Meijles, Daniel Nathan
Abstract
Acute kidney injury (AKI) is a major health problem affecting millions of patients globally. There is no effective treatment for AKI and new therapies are urgently needed. Novel drug development, testing and progression to clinical trials is overwhelmingly expensive. Drug repurposing is a more cost-effective measure. We identified 2 commonly used drugs (colchicine and metformin) that alter inflammatory cell function and signalling pathways characteristic of AKI, and tested them in models of acute and chronic kidney injury to assess therapeutic benefit. We assessed the renoprotective effects of colchicine or metformin in C57BL/6 mice challenged with renal ischemia reperfusion injury (IRI), treated before or after injury. All animals underwent analysis of renal function and biomolecular phenotyping at 24 h, 48 h and 4 weeks after injury. Murine renal tubular epithelial cells were studied in response to in vitro mimics of IRI. Pre-emptive treatment with colchicine or metformin protected against AKI, with lower serum creatinine, improved histological changes and decreased TUNEL staining. Pro-inflammatory cytokine profile and multiple markers of oxidative stress were not substantially different between groups. Metformin augmented expression of multiple autophagic proteins which was reversed by the addition of hydroxychloroquine. Colchicine led to an increase in inflammatory cells within the renal parenchyma. Chronic exposure after acute injury to either therapeutic agent in the context of reduced renal mass did not mitigate the development of fibrosis, with colchicine significantly worsening an ischemic phenotype. These data indicate that colchicine and metformin affect acute and chronic kidney injury differently. This has significant implications for potential drug repurposing, as baseline renal disease must be considered when selecting medication.
Item Type: |
Article
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Additional Information: |
Open Access This 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 Author(s) 2020 |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Sci Rep |
ISSN: |
2045-2322 |
Language: |
eng |
Dates: |
Date | Event |
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15 December 2020 | Published | 26 November 2020 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
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PubMed ID: |
33319836 |
Web of Science ID: |
WOS:000601309100025 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/112888 |
Publisher's version: |
https://doi.org/10.1038/s41598-020-78936-5 |
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