NDT Advance Access originally published online on April 19, 2005
Nephrology Dialysis Transplantation 2005 20(7):1320-1328; doi:10.1093/ndt/gfh837
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Angiotensin II stimulates 
3(IV) collagen production in mouse podocytes via TGF-ß and VEGF signalling: implications for diabetic glomerulopathy
1 Renal-Electrolyte and Hypertension Division of the University of Pennsylvania, Philadelphia, PA, 3 Division of Nephrology/Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, 2 Cellular Biology Unit, Department of Biology, Universidad Autónoma de Madrid, Spain and 4 Klinik für Innere Medizin III, University of Jena, Jena, Germany
Correspondence and offprint requests to: Sheldon Chen, MD, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-4218, USA. Email: chens{at}mail.med.upenn.edu
Background. The podocyte is bathed in an angiotensin II (AngII)-rich ultrafiltrate, but the impact of AngII on podocyte pathobiology is not well known. Because podocytes play a direct role in the glomerular basement membrane (GBM) thickening of diabetes, the 
3(IV) collagen chain was examined. Podocyte expression of 3(IV) collagen may involve the transforming growth factor-ß (TGF-ß) and vascular endothelial growth factor (VEGF) systems.
Methods. Cultured mouse podocytes were treated with various doses of AngII for selected periods of time, with or without inhibitors of TGF-ß and VEGF signalling, SB-431542 and SU5416, respectively. TGF-ß1 and VEGF were assayed by enzyme-linked immunosorbent assay (ELISA); 3(IV) collagen, TGF-ß type II receptor and phospho-Smad2 were assayed by immunoblotting.
Results. AngII 
10–10 M was found to stimulate the production of 3(IV) collagen significantly in as short a time as 3 h. The expression of 3(IV) collagen was influenced by the TGF-ß system, but AngII did not increase the podocyte's production of TGF-ß1 ligand; rather, it increased the expression of the TGF-ß type II receptor and activated the TGF-ß signalling system through Smad2. Despite the TGF-ß receptor upregulation, synergy between AngII and TGF-ß1 to boost 3(IV) collagen production was not observed. However, blockade of TGF-ß signalling with SB-431542 prevented AngII from stimulating 3(IV) collagen production. Podocyte expression of 3(IV) collagen was also increased by the autocrine activity of VEGF. Podocytes were stimulated to secrete VEGF by 10–10 M or higher AngII after 48 h. Blockade of the endogenous VEGF activity by SU5416 prevented AngII-stimulated 3(IV) collagen production.
Conclusions. AngII stimulates the podocyte to produce 3(IV) collagen protein via mechanisms involving TGF-ß and VEGF signalling. Alterations in 3(IV) collagen production may contribute to GBM thickening and perhaps proteinuria in diabetes.
Keywords: GBM thickening; proteinuria; SB-431542; Smad2; SU5416; TGF-ß type II receptor
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