Current studies 4

Diabetic nephropathy is the most general cause of end stage of kidney disease (renal failure), and has become the primary disease to the dialysis introduction from 1998 in Japan. Diabetic nephropathy has the profile which leads to the nodular glomerulosclerosis through mesangial cell proliferation and expansion and glomerular basement membrane thickening.

Cloning of the Megsin was carried out by Miyata in 1998 as a SERPIN specifically expressed in mesangial cells, and the overexpression was reported in human IgA glomerulonephritis and diabetic nephropathy which showed mesangial cell proliferation (J Am Soc Nephrol 1999). Moreover, the transgenic mouse overexpressing human megsin in the whole body has an onset of mesangial proliferative glomerulonephritis (J Clin Invest 2002) and the transgenic mouse crossbreed with diabetic mouse advanced nodular glomerulosclerosis which is characteristic of diabetic nephropathy. Recently ,it was reported that megsin highly expressed in the kidney of spontaneously diabetic rats, and the evidence suggests the intervention to diabetic nephropathy (Kidney Int 2008）. As mentioned above, the relation between megsin and the onset and progress of diabetic nephropathy is suggested, and it leaded to consider the possibility of the treatment concept of the diabetic nephropathy by the low molecular megsin inhibitor.

Then, in order to do screening of the megsin inhibitor, megsin expression system in E. Coli and its activity evaluation system in vitro were established. Furthermore, the assumed 4 sites of megsin inhibition were presumed from SBDD and candidate compounds were chosen from a small-scale commercial compound database (about 65,000) by the virtual docking simulation. The activity evaluation in vitro was performed and the hit compound has been obtained to use as a seed of future innovative drug development.