F(2)-isoprostanes mediate high glucose-induced TGF-beta synthesis and glomerular proteinuria in experimental type I diabetes

Kidney Int. 2000 Nov;58(5):1963-72. doi: 10.1111/j.1523-1755.2000.00368.x.


Background: The recently discovered arachidonic acid derivatives, isoprostanes, are increased in pathological conditions associated with oxidative stress, such as diabetes. No role has yet been described for isoprostanes during the development of diabetic nephropathy. Cell culture in high ambient glucose has been used as a model in elucidating cellular mechanisms underlying diabetic nephropathy. Among the growth factors involved in the effect of high glucose, transforming growth factor-beta (TGF-beta) has been described as playing a key role in the development of nephropathy.

Methods: Streptozotocin-induced diabetic rats were supplemented in their diet with the antioxidant vitamin E (1000 U/kg diet). Blood and urine samples were taken to determine renal function and isoprostane concentration, as determined by gas chromatography/mass spectrometry. Glomerular mesangial and endothelial cells were cultured in high ambient glucose to determine the synthesis of isoprostanes and the role of isoprostanes in high glucose-induced synthesis of TGF-beta.

Results: Streptozotocin-induced diabetic rats had marked increases in plasma levels and urinary excretion rates of F(2)-isoprostanes. Dietary supplementation with vitamin E normalized (plasma) and reduced (urine) isoprostane levels and, surprisingly, improved proteinuria and blood urea nitrogen (BUN) levels. High ambient glucose increased F(2)-isoprostane synthesis in glomerular endothelial and mesangial cells in culture. Incubation of glomerular cells with F(2)-isoprostanes stimulated the production of TGF-beta.

Conclusions: Increased F(2)-isoprostane synthesis during diabetes appears to be responsible in part for the increase in renal TGF-beta, a well-known mediator of diabetic nephropathy.

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

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / urine
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / urine
  • Dinoprost / analogs & derivatives*
  • Dinoprost / biosynthesis
  • Dinoprost / blood
  • Dinoprost / physiology*
  • Dinoprost / urine
  • Endothelium / cytology
  • Endothelium / drug effects
  • Endothelium / metabolism
  • F2-Isoprostanes
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / metabolism
  • Glucose / pharmacology
  • Glucose / physiology*
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Proteinuria / etiology*
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta / biosynthesis*


  • F2-Isoprostanes
  • Transforming Growth Factor beta
  • 8-epi-prostaglandin F2alpha
  • Dinoprost
  • Glucose