Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse.
- Publisher:
- NATURE PORTFOLIO
- Publication Type:
- Journal Article
- Citation:
- Sci Rep, 2021, 11, (1), pp. 12437
- Issue Date:
- 2021-06-14
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Nguyen, LT | |
dc.contributor.author | Saad, S | |
dc.contributor.author | Shi, Y | |
dc.contributor.author | Wang, R | |
dc.contributor.author | Chou, ASY | |
dc.contributor.author | Gill, A | |
dc.contributor.author | Yao, Y | |
dc.contributor.author | Jarolimek, W | |
dc.contributor.author | Pollock, CA | |
dc.date.accessioned | 2022-10-23T23:54:24Z | |
dc.date.available | 2021-05-17 | |
dc.date.available | 2022-10-23T23:54:24Z | |
dc.date.issued | 2021-06-14 | |
dc.identifier.citation | Sci Rep, 2021, 11, (1), pp. 12437 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | http://hdl.handle.net/10453/162610 | |
dc.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. | |
dc.format | Electronic | |
dc.language | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.relation.ispartof | Sci Rep | |
dc.relation.isbasedon | 10.1038/s41598-021-91772-5 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject.mesh | Amino Acid Oxidoreductases | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Cyclosporine | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Extracellular Matrix | |
dc.subject.mesh | Extracellular Matrix Proteins | |
dc.subject.mesh | Fibrosis | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Kidney Diseases | |
dc.subject.mesh | Kidney Tubules | |
dc.subject.mesh | Male | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Protective Agents | |
dc.subject.mesh | Protein-Lysine 6-Oxidase | |
dc.subject.mesh | Kidney Tubules | |
dc.subject.mesh | Extracellular Matrix | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Kidney Diseases | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Fibrosis | |
dc.subject.mesh | Cyclosporine | |
dc.subject.mesh | Amino Acid Oxidoreductases | |
dc.subject.mesh | Protein-Lysine 6-Oxidase | |
dc.subject.mesh | Extracellular Matrix Proteins | |
dc.subject.mesh | Protective Agents | |
dc.subject.mesh | Male | |
dc.title | Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse. | |
dc.type | Journal Article | |
utslib.citation.volume | 11 | |
utslib.location.activity | England | |
pubs.organisational-group | /University of Technology Sydney | |
utslib.copyright.status | open_access | * |
dc.date.updated | 2022-10-23T23:54:18Z | |
pubs.issue | 1 | |
pubs.publication-status | Published online | |
pubs.volume | 11 | |
utslib.citation.issue | 1 |
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.
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