期刊
KIDNEY INTERNATIONAL
卷 64, 期 2, 页码 468-479出版社
ELSEVIER SCIENCE INC
DOI: 10.1046/j.1523-1755.2003.00135.x
关键词
renal hypertrophy; growth factors; protein translation
资金
- NIDDK NIH HHS [DK55815] Funding Source: Medline
Background. Vascular endothelial growth factor (VEGF) is an important determinant of ocular complications of diabetes. Its potential role in diabetic renal disease has not been extensively studied. Methods. We employed mice with streptozotocin-induced type 1 diabetes and db/db mice with type 2 diabetes to study the regulation of renal VEGF. Studies of VEGF regulation of protein synthesis were performed using proximal tubular epithelial (MCT) cells in culture. Results. A nearly three-fold increase of VEGF165 expression in the renal cortex was seen, coinciding with renal hypertrophy in mice with either type 1 or type 2 diabetes. VEGF increased de novo protein synthesis and induced significant hypertrophy in MCT cells. VEGF stimulation of protein synthesis was dependent on tyrosine phosphorylation of the type 2 VEGF receptor and phosphatidylinositol 3-kinase (PI 3-kinase) activity. Activity of Akt was increased two- to three-fold by VEGF. Expression of dominant-negative Akt showed that Akt activation was also needed for VEGF-induced protein synthesis and cell hypertrophy. As PI 3-kinase-Akt axis regulates initial events in protein translation, these events were examined in the context of VEGF regulation of protein synthesis. VEGF stimulated eukaryotic initiation factor 4E-binding protein (4E-BP1) phosphorylation, which was dependent on activation of PI 3-kinase and Akt. Stable transfection with 4E-BP1 Thr(37,46) -Ala(37,46) mutant abolished the VEGF-induced de novo protein synthesis and cell hypertrophy. Conclusion. VEGF augments protein synthesis and induces hypertrophy in MCT cells in a PI 3-kinase- and Akt-dependent manner. Phosphorylation of Thr(37,46) in 4E-BP1 is required for VEGF-induced protein synthesis and hypertrophy in MCT cells. These data suggest a role for VEGF in the pathogenesis of diabetic renal disease.
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