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Kidney Int. 2003 Aug;64(2):468-79.

Vascular endothelial growth factor induces protein synthesis in renal epithelial cells: a potential role in diabetic nephropathy.

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1
South Texas Veterans' Health Care System and Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.

Abstract

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 Thr37,46-Ala37,46 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 Thr37,46 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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