ToxSci Advance Access originally published online on January 29, 2007
Toxicological Sciences 2007 96(2):346-356; doi:10.1093/toxsci/kfm010
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Rosiglitazone Prevents Advanced Glycation End Products–Induced Renal Toxicity Likely through Suppression of Plasminogen Activator Inhibitor-1
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* Department of Pathology, Institute of Frontier Medical Science, Jilin University, Changchun, China
Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Wenzhou, China
Departments of Medicine and Radiation Oncology, the University of Louisville, Louisville
1 To whom correspondence should be addressed at Department of Medicine, The University of Louisville, 511 South Floyd Street, MDR 533, Louisville, KY 40202. Fax: (502) 852-6904. E-mail: L0cai001{at}louisville.edu.
Received November 27, 2006; accepted January 22, 2007
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Abstract |
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In the development of diabetic nephropathy, advanced glycation end products (AGEs) play a causative role via induction of extracellular matrix (ECM) accumulation. Plasminogen activator inhibitor-1 (PAI-1), as a major inhibitor of plasminogen activator that plays an important role in degrading ECM, was found to significantly increase in renal fibrotic diseases. Activation of peroxisome proliferator-activated receptor (PPAR)-
prevented diabetic nephropathy. The present study, therefore, was to define whether or not AGE-induced renal ECM accumulation and renal dysfunction are mediated by upregulation of PAI-1 expression and whether or not PPAR- agonist can attenuate these AGE effects via suppressing PAI-1 expression. Rats were given AGEs alone by iv injection at 100 mg/kg daily with or without oral supplementation of PPAR- agonist rosiglitazone (RGZ) at 2 mg/kg daily for 6 weeks. Results showed that AGEs induced a renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) contents in glomeruli, and a mild renal dysfunction, as shown by an increase in urinary proteins. AGEs also caused an increase in PAI-1 expression and a decrease in plasminogen activator bioactivity in the kidney. Treatment with RGZ significantly ameliorated AGE-induced renal ECM accumulation, proteinuria, and PAI-1 upregulation. Direct exposure of rat mesangial cells to AGEs in vitro induced increases in fibronectin and Col IV syntheses along with an increase in PAI-1 expression, effects significantly attenuated by RGZ. Preincubation of PAI-1 antibody to AGE-treated mesangial cells completely prevented AGE-induced fibronectin and Col IV production. These results suggest that upregulation of PAI-1 expression plays a critical role in AGE-induced renal ECM accumulation. Renal protection of RGZ from AGEs may be associated with the suppression of PAI-1 expression through PPAR-dependent and independent mechanisms.
Key Words: advanced glycation end products; diabetic nephropathy; extracellular matrix accumulation; peroxisome proliferator-activated receptor-; plasminogen activator inhibitor-1.
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