Cellular and Molecular Biology



Role of Smad1 in diabetic nephropathy: Molecular mechanisms and implications as a diagnostic marker

Hideharu Abe1, Takeshi Matsubara2, Hidenori Arai3 and Toshio Doi1

1Department of Clinical Biology and Medicine, Graduate School of Bio-Health Science, The University of Tokushima, Tokushima, Japan and 2Department of Nephrology, and 3Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Offprint requests to: Hideharu ABE, MD, PhD, Department of Nephrology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan. e-mail: abeabe@clin.med.tokushima-u.ac.jp

Summary. Diabetic nephropathy (DN) is the leading cause of chronic kidney failure. Moreover, DN is associated with elevated cardiovascular morbidity and mortality. DN is characterized by progressive expansion of the mesangial matrix and thickening of the glomerular basement membrane, resulting in the obliteration of glomerular capillaries. Advanced glycation endproducts (AGEs) produced as the result of hyperglycemia are known to stimulate the production of extracellular matrix (ECM) proteins, resulting in glomerulosclerosis. Exposure of cultured mesangial cells to AGEs results in a receptor-mediated upregulation of mRNA and protein secretion of type IV collagen (Col4), which is a major component of ECM. Here we review recent novel insights into the pathogenesis and diagnosis of DN, with a special emphasis on the emerging concept that diabetic glomerulosclerosis can result from activation of the signaling cascade leading to irreversible ECM overproduction. Finally, we describe signaling pathways involved in the initial change of DN and how these pathways can be manipulated for therapeutic benefit.
Histol Histopathol 26, 531-541 (2011)

Key words: Diabetic nephropathy, Smad1, Type IV collagen, SMA, Biomarker

DOI: 10.14670/HH-26.531