tetronic-acid and Glomerulonephritis

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.

Topics: Administration, Intravenous; Animals; Antibodies, Monoclonal; Cell Proliferation; Creatinine; Furans; Glomerulonephritis; Inhibitory Concentration 50; Male; Mesangial Cells; Mice; Mixed Function Oxygenases; Rats; Rats, Wistar; Vitamin K Epoxide Reductases