Current clinical problems of diabetic nephropathy and novel approach from basic study

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease and the most important risk factor for cardiovascular events in the world. Microalbuminuria (MA) has been used as a key diagnosis marker for early phase DN, however, there are several problems for sensitivity and specificity for detecting early phase DN. Recent studies suggest that the glomerular structure in diabetic patients with or without MA failed to find a significant difference in the structural changes, even though MA definitely shows a key factor for cardiovascular events. DN is characterized by both mesangial matrix hyperplasia and thickening of glomerular basement membrane. The former finding has a strong correlation with decline of renal function, therefore, it is important to clarify the pathogenetic mechanism of mesangial matrix hyperplasia in DN. We have first shown that Smad1 is a transcription factor for α1 & 2 of type IV collagen (Col4), which is a major component of mesangial matrix hyperplasia. We have also identified Smad1 is a critical responsible molecule for developing mesangial matrix hyperplasia in rat DN. We also have found the good correlation between mesangial matrix hyperplasia and urinary Smad1 but not between mesangial matrix hyperplasia and urine albumin. The study also implicates that both bone morphogenic protein4 (BMP4)-Smad1 signaling pathway as well as angiotensin II (AngII)-Src-Smad1 signaling pathway have played a key role for development of DN. These suggest that it is necessary to clarify the whole mechanism related to Smad1 signaling to identify the pathogenesis of DN.