A novel vitamin K1 2,3-epoxide reductase (VKOR) inhibitor, 3-acetyl-5-methyltetronic acid, reduces experimental glomerulonephritis.

Abstract

Excessive proliferation of mesangial cells is observed in various types of glomerular disease including glomerulonephritis (GN), which is progressive in nature and eventually results in end-stage renal disease (ESRD). Vitamin K(1) 2,3-epoxide reductase (VKOR) and the vitamin K-dependent growth arrest-specific gene 6/Axl pathway play a key role in mesangial cell proliferation in GN. In the present study, we indicate the potential of a VKOR inhibitor, 3-acetyl-5-methyltetronic acid (AMT), to prevent the proliferation of glomerular mesangial cells and suppress the progression of GN. AMT was administered intravenously to rats once daily for 12 days and a mouse anti-Thy1 monoclonal antibody was injected intravenously after the AMT treatment on Day 6. Creatinine clearance (CCr) significantly increased and the albumin-to-creatinine ratio (ACR) significantly decreased in the AMT-treated group of the Thy-1 GN rats. In addition, glomerular and tubular damage was improved histopathologically in the AMT-treated group. AMT did not affect blood coagulation due to its unique pharmacokinetic properties. The concentration of AMT reached the IC(50) for VKOR in kidney, but not in liver. A novel VKOR inhibitor, AMT, reduced renal mesangial cell proliferation and could be a supportive treatment for GN.

• Authors: Masashi Uchida, Yuka Sakaguchi, Yohei Miyamoto
• Journal: The Journal of veterinary medical science (J Vet Med Sci) Vol. 74 Issue 7 Pg. 863-9 (Jul 2012) ISSN: 1347-7439 [Electronic] Japan
• PMID: 22322189 (Publication Type: Journal Article)

Chemical References

• 3-acetyl-5-methyltetronic acid
• Antibodies, Monoclonal
• Furans
• Creatinine
• Mixed Function Oxygenases
• Vitamin K Epoxide Reductases
• tetronic acid

Topics

• Administration, Intravenous
• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Cell Proliferation (drug effects)
• Creatinine (blood)
• Furans (administration & dosage, pharmacokinetics, pharmacology)
• Glomerulonephritis (drug therapy, pathology)
• Inhibitory Concentration 50
• Male
• Mesangial Cells (drug effects, physiology)
• Mice
• Mixed Function Oxygenases (antagonists & inhibitors)
• Rats
• Rats, Wistar
• Vitamin K Epoxide Reductases