Related Experiment Video
Updated: Nov 2, 2025
Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse
Long T Nguyen1, Sonia Saad2, Ying Shi2
1Renal Medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia. long.t.nguyen@sydney.edu.au.
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.
Insights
Cyclosporin (CsA) can cause kidney damage, but inhibiting lysyl oxidases (LOXs) shows promise. A Pan-LOX inhibitor, PXS-5505, effectively reduced CsA-induced nephropathy and improved renal function in mice.
Area of Science:
- Nephrology
- Pharmacology
- Biochemistry
Background:
- Calcineurin inhibitors like Cyclosporin (CsA) are vital for organ transplant rejection but can cause kidney damage (nephropathy).
- Lysyl oxidases (LOXs) enzymes are implicated in tissue scarring and extracellular matrix (ECM) crosslinking.
- Inhibiting LOXs may offer a therapeutic strategy against CsA-induced nephropathy.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting lysyl oxidases (LOXs) against Cyclosporin (CsA)-induced nephropathy in mice.
- To evaluate the efficacy of a Pan-LOX inhibitor (PXS-5505) and a LOX-like 2 (LOXL2) inhibitor (PXS-5382) in a mouse model of CsA-induced kidney injury.
Main Methods:
- C57BL/6J mice were treated with CsA for 16 weeks to induce nephropathy.
- CsA-treated mice received vehicle, Pan-LOX inhibitor (PXS-5505), LOXL2 inhibitor (PXS-5382), sequential therapy, or Telmisartan.
- Kidney injury, fibrosis, inflammation, oxidative stress, and molecular markers were assessed.
Main Results:
- CsA administration significantly increased blood urea nitrogen, kidney injury, tubulointerstitial fibrosis, inflammation, and oxidative stress.
- CsA upregulated mRNA expression of LOX and LOXL2.
- Pan-LOX inhibitor PXS-5505, LOXL2 inhibitor PXS-5382, and sequential therapy suppressed ECM proteins, matrix metalloproteinases, inflammatory markers, and TGF-β1-Smad3 signaling.
- Only the Pan-LOX inhibitor PXS-5505 attenuated elevated blood urea nitrogen levels.
Conclusions:
- Pan-LOX and LOXL2 inhibition can attenuate progressive nephropathy induced by CsA.
- The Pan-LOX inhibitor PXS-5505 demonstrated superior efficacy in improving renal function compared to other treatments, including Telmisartan.
More Related Videos
14:18Author Spotlight: Investigating the Potential of Chinese Herbal Medicinal Active Dioscin in Treating IgA Nephropathy
Published on: October 13, 2023
07:38Induction of Nephrotic Syndrome in Mice by Retrobulbar Injection of Doxorubicin and Prevention of Volume Retention by Sustained Release Aprotinin
Published on: May 6, 2018
Related Concept Videos
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:30Acute Kidney Injury IV: Diagnostic Studies and Prevention