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Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end-products (AGEs) stimulation

Abe H, Matsubara T, Iehara N, Nagai K, Takahashi T, Arai H, Kita T, Doi T
J Biol Chem. 2004 Apr 2;279(14):14201-6. Epub 2004 Jan 19.
Prolonged exposure to hyperglycemia is now recognized as the significantly causal factor of diabetic complications. Excessive advanced glycation end-products (AGEs) as a result of hyperglycemia in tissues or in the circulation may critically affect the progression of diabetic nephropathy. In diabetic nephropathy glomerulosclerosis is a typical pathologic feature characterised by the increase of extracellular matrix (ECM). We have previously reported that a1 type IV collagen (Col4) is one of the major components of ECM, which is up-regulated by AGEs, and that the overexpression of Col4 is transcriptionally regulated by an unknown transcription factor binding to the promoter. Here we identified this protein as Smad1 by yeast one-hybrid screening. Using chromatin immunoprecipitation (ChIP) and reporter assay, we observed that Smad1 directly regulated transcription for Col4 through the binding of Smad1 to the promoter of Col4. Smad1 was significantly induced along with Col4 in AGEs-treated mesangial cells. Moreover, suppression of Smad1 by antisense morpholino resulted in a decrease of AGEs-induced Col4 overproduction. To elucidate the interaction between transforming growth factor (TGF)-beta and Smad1, we investigated whether activin receptor-liked kinase1 (ALK1) was involved in this regulation. AGEs stimulation significantly increased the expression of the ALK1 mRNA in mesangial cells. We also demonstrated that Smad1 and ALK1 were highly expressed in human diabetic nephropathy. These results suggest that the modulation of Smad1 expression is responsible for initiation and progression of diabetic nephropathy and that blocking Smad1 signaling may be beneficial to prevent diabetic nephropathy and other various diabetic complications.
Organism or Cell Type: 
cell culture: mouse glomerular mesangial cells
Delivery Method: 
not published