Oxidative stress and dysregulation of the taurine transporter in high-glucose-exposed human Schwann cells: implications for pathogenesis of diabetic neuropathy.
In human Schwann cells, the role of taurine in regulating glucose-induced changes in antioxidant defense systems has been examined. Treatment with high glucose for 7 days induced reactive oxygen species, increased 4-hydroxynoneal adducts (20 +/- 5%, P < 0.05) and poly(ADP-ribosyl)ated proteins (40 +/- 13%, P < 0.05). Increases in these markers of oxidative stress were reversed by simultaneous incubation in 0.25 mM taurine. Both high glucose and taurine independently increased superoxide dismutase and catalase activity and decreased glutathione levels, but their effects were not additive. Glucose reduced taurine transporter (TauT) mRNA and protein in a dose-dependent manner with maximal decreases of 66 +/- 6 and 63 +/- 12%, respectively (P < 0.05 both). The V(max) for taurine uptake was decreased in 30 mM glucose from 61 +/- 5 to 42 +/- 3 pmol x min(-1) x mg protein(-1) (P < 0.001). Glucose-induced TauT downregulation could be reversed by inhibition of aldose reductase, a pathway that depletes NADPH and increases osmotic stress and protein glycation. TauT protein was increased more than threefold, and the V(max) for taurine uptake doubled (P < 0.05 both) by prooxidants. TauT downregulation was reversed both by treatment with the antioxidant alpha-lipoic acid, which increased TauT mRNA by 60% and V(max) by 50% (P < 0.05 both), and by the aldose reductase inhibitor sorbinil, which increased TauT mRNA 380% and V(max) by 98% (P < 0.01 both). These data highlight the potential therapeutic benefits of taurine supplementation in diabetic complications and provide mechanisms whereby taurine restoration could be achieved in order to prevent or reverse diabetic complications.
Askwith
Trevor
T
Dept. of Clinical and Experimental Medicine, Univ. of Birmingham, Birmingham, B15 2TT UK.
Zeng
Wei
W
Eggo
Margaret C
MC
Stevens
Martin J
MJ
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D003929:Diabetic Neuropathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013654:Taurine / Q000378:metabolism; D000099247:Taurine Transporters
D000449:Aldehyde Reductase; D000975:Antioxidants; D004791:Enzyme Inhibitors; D005947:Glucose; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D013654:Taurine; D000099247:Taurine Transporters