PA Activity And PAI-1 Expression Regulated By TGF-β1 Involved In The Development Of Diabetic Nephropathy

Diabetic nephropathy (DN) is characterized by the glomerularhypertrophy and thickening of glomerular and tubular basement membranesand progressive accumulation of extracellular matrix proteins in themesangium and the interstitium. transforming growth factor -β1 (TGF-β1),Plasminogen Activator (PA) and Plasminogen Activator Inhibitor (PAI-1)involved in the development of DN. Mesangial cells (MCs) are involved inthe fibrosis of kidney, but until now, there is no report which MCs is relatedwith TGF-β1,PA and PAI-1, so, the aim of this paper is to discuss therelationship between DN and TGF-β1, PA, PAI-1.This study is to investigate the changes of TGF-β1, PA and PAI-1 inthe patients of the different stages with type 2 diabetic nephropathy. PAI-1expression and activity induced with TGF-β1 were also examined in ratMCs in vitro. Meanwhile, the effect of TGF-β1 on PA and PAI-1 was alsoanalyzed in DN rat in vivo, and this study is to approach the effect ofTGF-β1, PA, PAI-1 on the development of DN.Serum TGF -β1was measured with enzyme -linked immunosersorbentassay in 8 patients with diabetic patients without DN, 7 patients withincipient DN, 9 patients with overt DN, and 6 control subjects. The resultsof clinical research showed that systolic pressure, diastolic pressure andurinary albumin excretion rate (UAER) in DN patients was higher than thatin control, fasting blood glucose, glycosylated hemoglobin, urea nitrogen,creatinine, triglyceride and high density lipoprotein in DN patients wassignificantly higher than that in control groups. The serum level of TGF-β1in DN patients was significantly higher than that in diabetic patientswithout DN and normal persons (P < 0.05 or P < 0.01). The serum level ofPAI-1 was also significantly higher and t-PA decreased in DN patients.Correlation analysis indicated that TGF -β1 was positively correlated withUAER and PAI-1 and was negtively correlated with t-PA.Omentum majus of healthy adult was used to culture MCs in primarygeneration, the third generation of cultured cells was stimulated by 5 ng/mlTGF-β1. MTT, FCS, Western blotting, ELISA and RT-PCR wereemployed to observe the mRNA and protein expressions of PAI-1, mRNAand t-PA activity respectively, transforming growth factor-β1 treated ratMesangial cells in vitro, can change the mRNA and protein expressions ofplasminogen activator inhibitor-1 (PAI-1) and PA activity. The dosage ofTGF-β1 lower than 5 ng/mL inhibited the growth of MCs and the dosage ofTGF-β1 higher than 5 ng/mL stimulated the growth of MCs and induce theexpression of PAI-1 and its mRNA and inhibited the activity of PA.The rat with Diabetic nephropathy was duplicated with Advancednonenzymed endproducts. High concentration of glucose increased TGF-β1biosynthesis. Renal glomerulus TGF-β1, PAI-1 and its mRNA significantlyincreased in DN rats, and tPA activity in cortex decreased significantly inrats. Pathological study showed that renal injury and fibrosis, etc.In conclusion, this study in vivo and in vitro domostrated that TGF -β1induced expression of PAI-1 and its mRNA, and further inhibited PAactivity, TGF-β1 activite the mesangial cells, and promoted theaccumulation of extracellular matrix and renal glomerulus fibrosis, TGF-β1play a very important role in the occurrence and development in DN.