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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/F1657    most recent 00274.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Wang, A. Articles by Chen, S. Search for Related Content PubMed PubMed Citation Articles by Wang, A. Articles by Chen, S.

Interference with TGF- signaling by Smad3-knockout in mice limits diabetic glomerulosclerosis without affecting albuminuria

¹Division of Nephrology/Hypertension, Northwestern University, Chicago, Illinois; ²Faculty of Medicine, American University of Beirut, Beirut, Lebanon; ³SoonChunHyang University College of Medicine, Cheonan, Korea; ⁴Department of Pathology, Ewha Womans University, Mok Dong Hospital, Seoul, Korea; ⁵Urogenital Biology, Cardiovascular Urogenital Centers of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

Submitted 14 June 2007 ; accepted in final form 29 August 2007

Transforming growth factor (TGF)- plays a critical role in diabetic nephropathy. To isolate the contribution of one of the signaling pathways of TGF-, the Smad3 gene in the mouse was knocked out at exons 2 and 3, and the effect was studied in streptozotocin (STZ)-induced diabetes over a period of 6 wk. TGF- activity was increased in the diabetic mice but was not able to signal via Smad3 in the knockout (KO) mice. As expected in the wild type, the kidneys of the STZ-diabetic mice showed both structural and functional defects that are characteristic of diabetic renal involvement. In the Smad3-KO mice, however, the defects that were improved were renal hypertrophy, mesangial matrix expansion, fibronectin overproduction, glomerular basement membrane thickening, plasma creatinine, and the blood urea nitrogen. The parameters not significantly altered by the Smad3-KO were albuminuria, reduction in podocyte slit pore density, and the increase in vascular endothelial growth factor abundance and activity. It seems that the absence of Smad3 modifies the natural course of murine diabetic nephropathy, providing renal functional protection and preventing structural lesions relating to kidney hypertrophy and matrix accumulation, even though albuminuria and changes in podocyte morphology persist. In conclusion, the effects of the Smad3-KO mirror the effects of anti-TGF- therapy in diabetes, suggesting that the chief component of TGF- signaling that is relevant to kidney disease is the Smad3 pathway.

streptozotocin; glomerular basement membrane thickening; mesangial matrix expansion; vascular endothelial growth factor; podocyte slit pore density

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