Alpha-lipoic acid upregulates antioxidant enzyme gene expression and enzymatic activity in diabetic rat kidneys through an O-GlcNAc-dependent mechanism.
OBJECTIVE
The combined hyperglycemia lowering and antioxidant actions of α-lipoic acid (LA) contribute to its usefulness in preventing renal injury and other diabetic complications. The precise mechanisms by which LA alters diabetic oxidative renal injury are not known. We hypothesized that LA through its hypoglycemic effect lowers O-GlcNAcylation which influences the expression and activities of antioxidant enzymes which assume important roles in preventing diabetes-induced oxidative renal injury.


METHODS
An experimental model of diabetes was induced in rats by the administration of 40 mg/kg streptozotocin (STZ) intraperitoneally (i.p.) for five consecutive days. LA was applied at a dose of 10 mg/kg i.p. for 4 weeks, starting from the last day of STZ administration.


RESULTS
An improved glycemic status of LA-treated diabetic rats was accompanied by a significant suppression of oxidative stress and a reduction of oxidative damage of lipids, proteins and DNA. LA treatment normalized CuZn-superoxide dismutase (SOD) and catalase activities in renal tissue of diabetic rats. These changes were allied with upregulated gene expression and lower levels of O-GlcNA glycosylation. The accompanying increase in MnSOD activity was only linked with upregulated gene expression. The observed antioxidant enzyme gene regulation was accompanied by nuclear translocation of Nuclear factor-erythroid-2-related factor 2 (Nrf2), enhanced expression of heat shock proteins (HSPs) and by reduction in O-GlcNAcylation of HSP90, HSP70, and extracellular regulated kinase and p38.


CONCLUSIONS
α-Lipoic acid administration activates a coordinated cytoprotective response against diabetes-induced oxidative injury in kidney tissue through an O-GlcNAc-dependent mechanism.
Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Bulevar despota Stefana 142, 10060, Belgrade, Serbia.
Jelena
J
Arambašić
Mirjana
M
Mihailović
Aleksandra
A
Uskoković
Svetlana
S
Dinić
Nevena
N
Grdović
Jelena
J
Marković
Goran
G
Poznanović
Djordje
D
Bajec
Melita
M
Vidaković
D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006031:Glycosylation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D007674:Kidney Diseases / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*; D015854:Up-Regulation
D000975:Antioxidants; D001786:Blood Glucose; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D013311:Streptozocin; D008063:Thioctic Acid; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; D000117:Acetylglucosamine