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

Kidney Int. 2003 Aug;64(2):468-79. doi: 10.1046/j.1523-1755.2003.00135.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Eukaryotic Initiation Factors
  • Hypertrophy
  • Kidney / metabolism*
  • Kidney / pathology
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Vascular Endothelial Growth Factor A / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factors
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Vascular Endothelial Growth Factor A
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt