The current clinical problems for early phase of diabetic nephropathy and approach for pathogenesis of diabetic nephropathy.

The important clinical problems of diabetic nephropathy are both proteinuria and decrease of renal function. Pathological analysis showed decrease of GFR was correlated to degree of mesangial expansion but not thickening of GBM nor the other findings in human type 1 diabetic nephropathy. From the perspective in renal dysfunction, mesangial matrix expansion was crucial for diabetic nephropathy. However, there was no difference of mesangial expansion between normal and microalbuminuria stage in type 1 and 2 diabetes mellitus (DM). On the other hand, microalbuminuria definitely shows a key related factor for cardiovascular events, but it does not indicate a clear interaction for glomerulosclerosis. We need to search a new clinical marker for renal injury. We have first shown that Smad1 is a transcription factor for alpha1 and 2 of type 4 collagen (Col4), which is a major component of glomerulosclerosis. We have also identified Smad1 is a critical responsible molecule for developing glomerulosclerosis in rat diabetic nephropathy. We have found the good correlation between glomerulosclerosis and urinary Smad1 but not between glomerulosclerosis and urine albumin. These data suggests that urine Smad1 is a promising clinical marker for underlying glomerular damages in early stage diabetic nephropathy. The study also implicates that angiotensin II (AngII)-Src-Smad1 signaling pathway has played a key role for development of diabetic nephropathy. These suggest that it is necessary to clarify the whole mechanism related to Smad1 to identify the pathogenesis of diabetic nephropathy.