Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse

Abstract Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Lysyl oxidases (LOXs), a group of enzymes that catalyse...

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Autores principales:	Long T. Nguyen, Sonia Saad, Ying Shi, Rosy Wang, Angela S. Y. Chou, Anthony Gill, Yimin Yao, Wolfgang Jarolimek, Carol A. Pollock
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1d8b0be6924f440380930771f436d6c4
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spelling	oai:doaj.org-article:1d8b0be6924f440380930771f436d6c42021-12-02T17:41:06ZLysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse10.1038/s41598-021-91772-52045-2322https://doaj.org/article/1d8b0be6924f440380930771f436d6c42021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91772-5https://doaj.org/toc/2045-2322Abstract Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Lysyl oxidases (LOXs), a group of enzymes that catalyse extracellular matrix (ECM) crosslinking, were shown to implicate in tissue scarring. It is hypothesized that inhibition of these enzymes may render therapeutic effects against CsA-induced nephropathy. In this study, 6-to-8 weeks old C57BL/6 J mice were administered saline or CsA (30 mg/kg/day s.c) for 16 weeks. At 8 weeks, CsA-treated animals were divided into 5 groups respectively treated with: (1) vehicle, (2) PXS-5505 (Pan-LOX inhibitor), (3) PXS-5382 (LOX-like 2 inhibitor), (4) PXS-5505 for 4 weeks then PXS-5382 for 4 weeks (sequential therapy), and (5) Telmisartan (standard therapy). Our results indicate that CsA administration significantly increased the levels of blood urea nitrogen, glomerular and tubular injury, tubulointerstitial fibrosis, inflammation and oxidative stress in mouse kidney. These changes were associated with upregulated mRNA expression of LOX and LOXL2. Administration of Pan-LOX or LOXL2 inhibitors or the sequential therapy suppressed the expression of ECM proteins (α-SMA, FN and COL1A), matrix metalloproteases (MMP)2 and 9, inflammatory markers (TNFα and MCP-1) and TGF-β1-Smad3 signalling. Among all regimens including telmisartan, only Pan-LOX inhibitor PXS-5505 was able to attenuate uraemia. Collectively, our study suggests that Pan-LOX and LOXL2 inhibition can attenuate progressive nephropathy due to CsA administration.Long T. NguyenSonia SaadYing ShiRosy WangAngela S. Y. ChouAnthony GillYimin YaoWolfgang JarolimekCarol A. PollockNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Long T. Nguyen Sonia Saad Ying Shi Rosy Wang Angela S. Y. Chou Anthony Gill Yimin Yao Wolfgang Jarolimek Carol A. Pollock Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse
description	Abstract Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Lysyl oxidases (LOXs), a group of enzymes that catalyse extracellular matrix (ECM) crosslinking, were shown to implicate in tissue scarring. It is hypothesized that inhibition of these enzymes may render therapeutic effects against CsA-induced nephropathy. In this study, 6-to-8 weeks old C57BL/6 J mice were administered saline or CsA (30 mg/kg/day s.c) for 16 weeks. At 8 weeks, CsA-treated animals were divided into 5 groups respectively treated with: (1) vehicle, (2) PXS-5505 (Pan-LOX inhibitor), (3) PXS-5382 (LOX-like 2 inhibitor), (4) PXS-5505 for 4 weeks then PXS-5382 for 4 weeks (sequential therapy), and (5) Telmisartan (standard therapy). Our results indicate that CsA administration significantly increased the levels of blood urea nitrogen, glomerular and tubular injury, tubulointerstitial fibrosis, inflammation and oxidative stress in mouse kidney. These changes were associated with upregulated mRNA expression of LOX and LOXL2. Administration of Pan-LOX or LOXL2 inhibitors or the sequential therapy suppressed the expression of ECM proteins (α-SMA, FN and COL1A), matrix metalloproteases (MMP)2 and 9, inflammatory markers (TNFα and MCP-1) and TGF-β1-Smad3 signalling. Among all regimens including telmisartan, only Pan-LOX inhibitor PXS-5505 was able to attenuate uraemia. Collectively, our study suggests that Pan-LOX and LOXL2 inhibition can attenuate progressive nephropathy due to CsA administration.
format	article
author	Long T. Nguyen Sonia Saad Ying Shi Rosy Wang Angela S. Y. Chou Anthony Gill Yimin Yao Wolfgang Jarolimek Carol A. Pollock
author_facet	Long T. Nguyen Sonia Saad Ying Shi Rosy Wang Angela S. Y. Chou Anthony Gill Yimin Yao Wolfgang Jarolimek Carol A. Pollock
author_sort	Long T. Nguyen
title	Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse
title_short	Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse
title_full	Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse
title_fullStr	Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse
title_full_unstemmed	Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse
title_sort	lysyl oxidase inhibitors attenuate cyclosporin a-induced nephropathy in mouse
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1d8b0be6924f440380930771f436d6c4
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Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse

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