| Summary: | 碩士 === 國立臺灣大學 === 毒理學研究所 === 95 === Diabetic nephropathy (DN) is one of the most devastating microvascular complications of diabetes as well as the leading cause of end-stage renal disease (ESRD) in the United States. Approximately 20 to 40% of the patients with type 1 diabetes and 10 to 20% of those with type 2 diabetes develop nephropathy. The earliest pathologic changes of DN are characterized by glomerular hypertrophy, mesangial expansion with the thickening of glomerular basement, expanded extracellular matrix (ECM), and glomerular sclerosis, which ultimately cause the progression of proteinuria and renal failure. Data from animal models as well as cultured renal cells the hyperglycemia and high glucose induced hypertrophy and extracellular matrix expansion. The molecular mechanisms of hyperglycemia-induced glomerular hypertrophy remain unknown.
In the present study, we first examined the effects of high glucose on glomerular hypertrophy in vitro. We found that isolated renal glomeruli treated with high glucose enhanced the protein/DNA ratio, glomerular volume, reactive oxygen species (ROS) production, PGE2 production and fibronectin expression. Moreover, high glucose also triggered the phosphorylation of Akt, activation of nuclear factor-κB, cyclooxygenase-2 (COX-2) expression, transforming growth factor-β1 (TGF-β1) expression, and p27kip1 expression in isolated renal glomeruli. Antioxidant N-acetylcysteine, phosphoinositide 3-kinase inhibitor LY294002, and COX-2 inhibitor NS398 significantly reversed the high glucose-induced increase of protein/DNA ratio, and glomerular volume.
On the other hand, we examined the effect of hyperglycemia on glomerular hypertrophy in vivo. We found that enhanced the kidney weight/body weight ratio, protein/DNA ratio, glomerular volume, BUN, and creatinine were increased in isolated glomeruli of streptozotocin -diabetic rats. Moreover, the phosphorylation of Akt, cyclooxygenase-2
(COX-2) expression, fibronectin expression, and p27kip1 expression in isolated glomeruli of diabetic rats were also triggered. Treatment with antioxidant N-acetylcysteine and COX-2 inhibitor meloxicam significantly reversed the increased in kidney weight/body weight ratio, protein/DNA
ratio, and glomerular volume in isolated glomruli of diabetic tars.
In conclusion, these results indicate that ROS/Akt/NF-κB/COX-2/PGE2/TGF-β1/ p27kip1signaling pathway may play an important role in hyperglycemia-induced renal glomeruli hypertrophy.
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