A Novel Vitamin K1 2,3-Epoxide Reductase (VKOR) Inhibitor, 3-Acetyl-5-Methyltetronic Acid, Reduces Experimental Glomerulonephritis

Journal of Veterinary Medical Science

Masashi UCHIDA¹  Yuka SAKAGUCHI¹  Yohei MIYAMOTO¹ 

[1] Toxicology and Pharmacokinetics Laboratories, Pharmaceutical Research Laboratories, Toray Industries, Inc., 6–10–1 Tebiro, Kamakura, Kanagawa 248–8555, Japan

关键词: 3-acetyl-5-methyltetronic acid (AMT);    glomerulonephritis (GN);    mesangial cell;    Thy-1;    vitamin K1 2;    3-epoxide reductase (VKOR);   

DOI  :  10.1292/jvms.11-0530

学科分类：兽医学

来源: Japanese Society of Veterinary Science

【 摘 要 】

References(45)Cited-By(3)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 K1 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 IC50 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.

【 授权许可】

Unknown