ToxSci Advance Access published online on January 29, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm010
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Rosiglitazone prevents advanced glycation endproducts-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1
a Department of Pathology, Institute of Frontier Medical Science, Jilin University, Changchun, China b Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Wenzhou, China c Departments of Medicine and Radiation Oncology, the University of Louisville, Louisville, USA
* Address correspondence and reprint requests to: Dr. Cai Li, Department of Pathology, Institute of Frontier Medical Science, Jilin University, Changchun, 130021, P.R. China, Phone: 011-86-(431) 5619702; E-mail: licaijia{at}public.cc.jl.cn Or Dr. Lu Cai, Department of Medicine, the University of Louisville, 511 South Floyd Street, MDR 533, Louisville, KY 40202, Phone: (502) 852-5215; 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 up-regulation 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 i.v. injection at 100 mg/kg daily with or without oral supplementation of PPAR agonist rosiglitazone (RGZ) at 2 mg/kg daily for six 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 up-regulation. 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. Pre-incubation of PAI-1 antibody to AGE-treated mesangial cells completely prevented AGE-induced fibronectin and Col IV production. These results suggest that up-regulation 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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