Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury

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 m...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Maryam El-Rashid, Danny Nguyen-Ngo, Nikita Minhas, Daniel N. Meijles, Jennifer Li, Kedar Ghimire, Sohel Julovi, Natasha M. Rogers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ef53a9104a44465b8875a257fc27d12a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ef53a9104a44465b8875a257fc27d12a
record_format	dspace
spelling	oai:doaj.org-article:ef53a9104a44465b8875a257fc27d12a2021-12-02T12:03:14ZRepurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury10.1038/s41598-020-78936-52045-2322https://doaj.org/article/ef53a9104a44465b8875a257fc27d12a2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78936-5https://doaj.org/toc/2045-2322Abstract 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.Maryam El-RashidDanny Nguyen-NgoNikita MinhasDaniel N. MeijlesJennifer LiKedar GhimireSohel JuloviNatasha M. RogersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maryam El-Rashid Danny Nguyen-Ngo Nikita Minhas Daniel N. Meijles Jennifer Li Kedar Ghimire Sohel Julovi Natasha M. Rogers Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury
description	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.
format	article
author	Maryam El-Rashid Danny Nguyen-Ngo Nikita Minhas Daniel N. Meijles Jennifer Li Kedar Ghimire Sohel Julovi Natasha M. Rogers
author_facet	Maryam El-Rashid Danny Nguyen-Ngo Nikita Minhas Daniel N. Meijles Jennifer Li Kedar Ghimire Sohel Julovi Natasha M. Rogers
author_sort	Maryam El-Rashid
title	Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury
title_short	Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury
title_full	Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury
title_fullStr	Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury
title_full_unstemmed	Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury
title_sort	repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/ef53a9104a44465b8875a257fc27d12a
work_keys_str_mv	AT maryamelrashid repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury AT dannynguyenngo repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury AT nikitaminhas repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury AT danielnmeijles repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury AT jenniferli repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury AT kedarghimire repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury AT soheljulovi repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury AT natashamrogers repurposingofmetforminandcolchicinerevealsdifferentialmodulationofacuteandchronickidneyinjury
_version_	1718394783218532352

Repurposing of metformin and colchicine reveals differential modulation of acute and chronic kidney injury

Ejemplares similares