Recent progress in understanding the molecular pathogenesis of diabetic nephropathy

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and a major contributor to morbidity and mortality of diabetic patients throughout the world. Albuminuria is one of the most characteristic functional changes in the early phase of DN. However, many recent studies have shown that there was no clear association between glomerulosclerosis and albuminuria in type 1 and 2 diabetes. DN is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli and is morphologically characterized by progressive expansion of mesangial matrix and thickening of the glomerular basement membrane. Type IV collagen (Col4) is a major component of the extracellular matrix (ECM) in the expanded mesangial matrix. Advanced glycation endproducts (AGEs) produced as the result of hyperglycemia are known to stimulate the production of ECM proteins in mesangial cells, resulting in glomerulosclerosis. Using a yeast one-hybrid screening, Smad1 was identified as a transcriptional regulator of Col4 in AGE-treated mesangial cells. Smad1 also regulated other ECM proteins, such as type I collagen and osteopontin, as well as alpha smooth muscle actin. Moreover, there was a very good correlation between urinary Smad1 levels and the development of mesangial expansion, whereas the correlation between albuminuria and mesangial expansion was not significant in experimental DN models. In addition, urinary Smad1 was revealed to be a good predictor for later onset of morphological changes and to be used to monitor the effect of ARB in DN. In conclusion, urinary Smad1 is expected to be a useful diagnostic biomarker for DN.