1. Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes
- Author
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Belinda Jim, Yuki Kasama, Joseph S. Lee, Maria Marin, Fuad N. Ziyadeh, and Sheldon Chen
- Subjects
Collagen Type IV ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Molecular Sequence Data ,Biology ,Autoantigens ,Podocyte ,Transforming Growth Factor beta1 ,chemistry.chemical_compound ,Mice ,Transforming Growth Factor beta ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Autocrine signalling ,DNA Primers ,Vascular Endothelial Growth Factor Receptor-1 ,Base Sequence ,urogenital system ,Reverse Transcriptase Polymerase Chain Reaction ,Glomerular basement membrane ,Cell Differentiation ,Epithelial Cells ,Transforming growth factor beta ,Recombinant Proteins ,Cell biology ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Endocrinology ,chemistry ,biology.protein ,Signal transduction ,Transforming growth factor ,Signal Transduction - Abstract
Podocyte-derived vascular endothelial growth factor (VEGF) is upregulated in diabetes and may contribute to albuminuria. Although believed to act upon the glomerular endothelium, VEGF may have pronounced effects on the podocyte itself. The functionality of this VEGF autocrine loop was investigated in conditionally immortalized mouse podocytes. Exogenous VEGF(164) increased the production of alpha3(IV) collagen, an integral component of the glomerular basement membrane (GBM); this effect was completely prevented by SU5416, a pan-VEGF receptor inhibitor. The VEGF inhibitor also partially prevented the stimulation of alpha3(IV) collagen by transforming growth factor (TGF)-beta1, establishing a novel role for endogenous VEGF. However, VEGF did not influence the production of another novel chain of collagen IV, alpha5(IV) collagen, and SU5416 failed to reverse the known inhibitory effect of TGF-beta1 on alpha5(IV) collagen production. Cultured mouse podocytes possess at least the VEGFR-1 receptor, confirmed by RT-PCR, immunoblotting, and immunocytochemistry. By these techniques, however, VEGFR-2 is absent. VEGF signaling proceeds via autophosphorylation of VEGFR-1 and activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Thus, podocyte-derived VEGF operates in an autocrine loop, likely through VEGFR-1 and PI3K, to stimulate alpha3(IV) collagen production. The TGF-beta1-stimulated endogenous VEGF may have significant implications for podocyte dysfunction in diabetic glomerulopathy, manifesting as GBM thickening and altered macromolecular permeability.
- Published
- 2004