Document Detail

Hexosamine induction of oxidative stress, hypertrophy and laminin expression in renal mesangial cells: effect of the anti-oxidant alpha-lipoic acid.
MedLine Citation:
PMID:  16892452     Owner:  NLM     Status:  MEDLINE    
We have previously shown that one of the potential mediators of the deleterious effects of high glucose on extracellular matrix protein (ECM) expression in renal mesangial cells is its metabolic flux through the hexosamine biosynthesis pathway (HBP). Here, we investigate further whether the hexosamines induce oxidative stress, cell-cycle arrest and ECM expression using SV-40-transformed rat mesangial (MES) cells and whether the anti-oxidant alpha-lipoic acid will reverse some of these effects. Culturing renal MES cells with high glucose (HG, 25 mM) or glucosamine (GlcN, 1.5 mM) for 48 h stimulates laminin gamma1 subunit expression significantly approximately 1.5 +/- 0.2- and 1.9 +/- 0.3-fold, respectively, when compared to low glucose (LG, 5 mM). Similarly, HG and GlcN increase the level of G0/G1 cell-cycle progression factor cyclin D1 significantly approximately 1.7 +/- 0.2- and 1.4 +/- 0.04-fold, respectively, versus LG (p < 0.01 for both). Azaserine, an inhibitor of glutamine:fruc-6-PO(4) amidotransferase (GFAT) in the HBP, blocks the HG-induced expression of laminin gamma1 and cyclin D1, but not GlcN's effect because it exerts its metabolic function distal to GFAT. HG and GlcN also elevate reactive oxygen species (ROS) generation, pro-apoptotic caspase-3 activity, and lead to mesangial cell death as revealed by TUNEL and Live/Dead assays. FACS analysis of cell-cycle progression shows that the cells are arrested at G1 phase; however, they undergo cell growth and hypertrophy as the RNA/DNA ratio is significantly (p < 0.05) increased in HG or GlcN-treated cells relative to LG. The anti-oxidant alpha-lipoic acid (150 microM) reverses ROS generation and mesangial cell death induced by HG and GlcN. Alpha-lipoic acid also reduces HG and GlcN-induced laminin gamma1 and cyclin D1 expression in MES cells. In addition, induction of diabetes in rats by streptozotocin (STZ) increases both laminin gamma1 and cyclin D1 expression in the renal cortex and treatment of the diabetic rats with alpha-lipoic acid (400 mg kg(-1) body weight) reduces the level of both proteins significantly (p < 0.05) when compared to untreated diabetic rats. These results support the hypothesis that the hexosamine pathway mediates mesangial cell oxidative stress, ECM expression and apoptosis. Anti-oxidant alpha-lipoic acid reverses the effects of high glucose, hexosamine and diabetes on oxidative stress and ECM expression in mesangial cells and rat kidney.
Lalit P Singh; Davis W Cheng; Renu Kowluru; Edi Levi; Yan Jiang
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell biochemistry and function     Volume:  25     ISSN:  0263-6484     ISO Abbreviation:  Cell Biochem. Funct.     Publication Date:    2007 Sep-Oct
Date Detail:
Created Date:  2007-08-29     Completed Date:  2007-11-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8305874     Medline TA:  Cell Biochem Funct     Country:  England    
Other Details:
Languages:  eng     Pagination:  537-50     Citation Subset:  IM    
Department of Anatomy/Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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MeSH Terms
Antioxidants / pharmacology
Apoptosis / drug effects
Caspase 3 / metabolism
Cell Cycle / drug effects
Cell Line
Cell Survival / drug effects
Cyclin D1 / metabolism
Diabetes Mellitus, Experimental
Glucosamine / pharmacology*
Glucose / pharmacology
Laminin / metabolism*
Mesangial Cells / cytology,  drug effects,  metabolism*,  pathology*
Oxidative Stress / drug effects*
Reactive Oxygen Species / metabolism
Thioctic Acid / pharmacology*
Reg. No./Substance:
0/Antioxidants; 0/Laminin; 0/Reactive Oxygen Species; 0/laminin gamma 1; 136601-57-5/Cyclin D1; 3416-24-8/Glucosamine; 50-99-7/Glucose; 62-46-4/Thioctic Acid; 63231-63-0/RNA; 9007-49-2/DNA; EC 3.4.22.-/Caspase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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