Rosiglitazone prevents advanced glycation end products-induced renal toxicity likely through suppression of plasminogen activator inhibitor-1.
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)-gamma 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-gamma 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-gamma 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.
Yu
Xiaoyan
X
Department of Pathology, Institute of Frontier Medical Science, Jilin University, Changchun, China.
Li
Cai
C
Li
Xiaokun
X
Cai
Lu
L
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000633:toxicity*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008854:Microscopy, Electron; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
D024141:Collagen Type IV; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone