These studies expand the potential scope of the pathophysiologic significance of F2-isoprostanes, released during oxidant injury, to include alteration of endothelial cell biology.

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.

F 2-isoprostanes mediate high glucose-induced TGF-␤ synthesis serious long-term complications for the individual diaand glomerular proteinuria in experimental type I diabetes. betic patient. More than one third of patients who de-Background. The recently discovered arachidonic acid develop chronic renal failure in the United States do so rivatives, isoprostanes, are increased in pathological conditions because of diabetes [1]. associated with oxidative stress, such as diabetes. No role has Diabetic nephropathy is characterized by the early yet been described for isoprostanes during the development of diabetic nephropathy. Cell culture in high ambient glucose appearance of hypertrophy of both glomerular and tubuhas been used as a model in elucidating cellular mechanisms lar structures, the subsequent development of thickened underlying diabetic nephropathy. Among the growth factors glomerular and tubular membranes associated with eninvolved in the effect of high glucose, transforming growth hanced glomerular permeability to albumin, and the factor-␤ (TGF-␤) has been described as playing a key role in eventual progressive accumulation of extracellular mathe development of nephropathy. Methods. Streptozotocin-induced diabetic rats were suppletrix components in the glomerular mesangium and the mented in their diet with the antioxidant vitamin E (1000 U/kg tubulointerstitium in susceptible patients [1]. diet). Blood and urine samples were taken to determine renal Cell culture has been widely used as an in vitro model function and isoprostane concentration, as determined by gas to assess the effects of hyperglycemia on cell functions. chromatography/mass spectrometry. Glomerular mesangial and Elevated ambient glucose influences renal cell growth endothelial cells were cultured in high ambient glucose to determine the synthesis of isoprostanes and the role of isoprosand extracellular matrix metabolism [2-4]. High glucose tanes in high glucose-induced synthesis of TGF-␤. stimulates proximal tubular cell hypertrophy and pro-Results. Streptozotocin-induced diabetic rats had marked induction of collagen types I and IV [5]. High glucose creases in plasma levels and urinary excretion rates of F 2-isoprosalso modulates mesangial cell growth and stimulates the tanes. Dietary supplementation with vitamin E normalized (plasma) and reduced (urine) isoprostane levels and, surpris-production of fibronectin and collagen [3, 4]. Both iningly, improved proteinuria and blood urea nitrogen (BUN) creased synthesis and decreased degradation have been levels. High ambient glucose increased F 2-isoprostane synthesis proposed to explain extracellular matrix accumulation in glomerular endothelial and mesangial cells in culture. Incuin the diabetic kidney [6, 7]. bation of glomerular cells with F 2-isoprostanes stimulated the It now appears that the hypertrophic and prosclerotic production of TGF-␤. Conclusions. Increased F 2-isoprostane synthesis during diaeffects of high glucose concentrations on glomerular betes appears to be responsible in ...

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