title: Role of Smad1 in diabetic nephropathy: Molecular mechanisms and implications as a diagnostic marker.
abstract: 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.
authors.affiliation: Department of Clinical Biology and Medicine, Graduate School of Bio-Health Science, The University of Tokushima, Tokushima, Japan. abeabe@clin.med.tokushima-u.ac.jp
authors.forename: Hideharu
authors.initials: H
authors.lastname: Abe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsubara
authors.forename: Hidenori
authors.initials: H
authors.lastname: Arai
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D024141:Collagen Type IV; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; C497399:SMAD1 protein, human; D051898:Smad1 Protein