Document Detail

Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 up-regulation in mesangial cells and in diabetic kidney.
MedLine Citation:
PMID:  15840023     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in remodeling of extracellular matrix (ECM) in the glomeruli. PAI-1 is up-regulated by high glucose and is overexpressed in diabetic kidney. Since reactive oxygen species (ROS) mediate ECM accumulation in diabetic glomeruli and was recently found to mediate transforming growth factor-beta1 (TGF-beta1)-induced PAI-1 up-regulation in glomerular mesangial cells, we examined the role of ROS in high glucose-induced PAI-1 expression in cultured glomerular mesangial cells and in streptozotocin-induced diabetic rat glomeruli. METHODS: Growth arrested and synchronized primary rat mesangial cells were treated with different concentrations of glucose in the presence or absence of N-acetylcysteine (NAC) or trolox, or after cellular reduced form of glutathione (GSH) depleted with DL-buthionine-(S,R)-sulfoximine (BSO). Taurine was administered to diabetic rats from 2 days to 4 weeks after streptozotocin injection. Urinary protein excretion, glomerular volume, and fractional mesangial area were measured as markers of renal injury and lipid peroxide (LPO) as an oxidative stress marker. PAI-1 mRNA expression was measured by Northern blot analysis in mesangial cells and reverse transcription-polymerase chain reaction (RT-PCR) in glomeruli, PAI-1 protein by Western blot analysis and enzyme-linked immunosorbent assay (ELISA), and plasmin activity by fluorometry. RESULTS: High glucose significantly increased PAI-1 mRNA and protein expression and decreased plasmin activity in mesangial cells. Equimolar concentrations of l-glucose or mannitol did not affect PAI-1 expression. BSO pretreatment significantly increased basal PAI-1 expression and amplified the response to high glucose. NAC effectively inhibited high glucose-induced, but not basal, PAI-1 expression. Reduced plasmin activity in mesangial cells by high glucose was rescued by antioxidants. Anti-TGF-beta antibody inhibited both high glucose- and H(2)O(2)-induced PAI-1 up-regulation. Taurine significantly reduced plasma LPO, glomerular PAI-1 expression, glomerular volume, fractional mesangial area, and proteinuria in streptozotocin-induced diabetic rats. CONCLUSION: These results demonstrate that ROS mediate high glucose-induced up-regulation of PAI-1 expression in cultured mesangial cells and in diabetic glomeruli. Since both high glucose and TGF-beta1 induce cellular ROS and ROS mediate both high glucose- and TGF-beta1-induced PAI-1, ROS appear to amplify TGF-beta1 signaling in high glucose-induced PAI-1 up-regulation. Antioxidants can prevent accumulation of ECM protein in diabetic glomeruli partly by abrogating up-regulation of PAI-1 and suppression of plasmin activity.
Eun Ah Lee; Ji Yeon Seo; Zongpei Jiang; Mi Ra Yu; Min Kyung Kwon; Hunjoo Ha; Hi Bahl Lee
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Kidney international     Volume:  67     ISSN:  0085-2538     ISO Abbreviation:  Kidney Int.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-20     Completed Date:  2005-08-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1762-71     Citation Subset:  IM    
Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
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MeSH Terms
Antioxidants / pharmacology
Base Sequence
Buthionine Sulfoximine / pharmacology
Cells, Cultured
DNA, Complementary / genetics
Diabetes Mellitus, Experimental / genetics,  metabolism
Diabetic Nephropathies / genetics*,  metabolism*
Fibrinolysin / metabolism
Glomerular Mesangium / drug effects,  metabolism*
Glucose / metabolism*,  pharmacology
Glutathione / metabolism
Oxidative Stress
Plasminogen Activator Inhibitor 1 / genetics*,  metabolism
RNA, Messenger / genetics,  metabolism
Rats, Sprague-Dawley
Reactive Oxygen Species / metabolism*
Taurine / pharmacology
Transforming Growth Factor beta / antagonists & inhibitors,  metabolism
Transforming Growth Factor beta1
Up-Regulation / drug effects
Reg. No./Substance:
0/Antioxidants; 0/DNA, Complementary; 0/Plasminogen Activator Inhibitor 1; 0/RNA, Messenger; 0/Reactive Oxygen Species; 0/Tgfb1 protein, rat; 0/Transforming Growth Factor beta; 0/Transforming Growth Factor beta1; 107-35-7/Taurine; 50-99-7/Glucose; 5072-26-4/Buthionine Sulfoximine; 70-18-8/Glutathione; EC

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