Oxidative stress and dysregulation of the taurine transporter in high-glucose-exposed human Schwann cells: implications for pathogenesis of diabetic neuropathy

Abstract

Askwith T, Zeng W, Eggo MC, Stevens MJ. Oxidative stress and dysregulation of the taurine transporter in high-glucose-exposed human Schwann cells: implications for pathogenesis of diabetic neuropathy. Am J Physiol Endocrinol Metab 297: E620 -E628, 2009. First published July 14, 2009; doi:10.1152/ajpendo.00287.2009.-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 Ϯ 5%, P Ͻ 0.05) and poly-(ADP-ribosyl)ated proteins (40 Ϯ 13%, P Ͻ 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 Ϯ 6 and 63 Ϯ 12%, respectively (P Ͻ 0.05 both). The Vmax for taurine uptake was decreased in 30 mM glucose from 61 Ϯ 5 to 42 Ϯ 3 pmol ⅐ min Ϫ1 ⅐ mg protein Ϫ1(P Ͻ 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 Vmax for taurine uptake doubled (P Ͻ 0.05 both) by prooxidants. TauT downregulation was reversed both by treatment with the antioxidant ␣-lipoic acid, which increased TauT mRNA by 60% and Vmax by 50% (P Ͻ 0.05 both), and by the aldose reductase inhibitor sorbinil, which increased TauT mRNA 380% and Vmax by 98% (P Ͻ 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.THE RELATIONSHIP OF HYPERGLYCEMIA to the microvascular complications of diabetes is well established (13a, 76a, 76b), but the mechanisms contributing to the development and progression of complications are not well understood. Recently, increased oxidative/nitrosative stress has been implicated as a key pathogenetic pathway (9,18,62,78). Increased oxidative stress has been identified in the nerve (4, 24, 68), eye (54), vasculature (31), kidney (3, 32), and heart (29) in diabetic rodent models and in diabetic patients (23,25,43,44). Antioxidant approaches have been shown to prevent or reverse complications in experimental diabetes (50). Glucose-driven oxidative stress occurs due to an imbalance in the production of reactive oxygen species (ROS) in concert with impaired antioxidant defense. Excess ROS production can have many downstream pathogenic effects within the cell, including protein nitrosylation, formation of poly(ADP-ribosyl)ated (PAR) protein polymers, and apoptosis (22,35,49,51,56,63). Flux through the enzyme aldose reductase (AR) pathway at key sites for di...

Taurine transporter gene expression in peripheral mononuclear blood cells of type 2 diabetic patients

“…Glucose-induced TauT downregulation in human Schwann cells is reversed by inhibition of aldose reductase as well as by protein kinase C (PKC) inhibitors indicating the importance in the process of both osmolality (Askwith et al 2009) and of glucose-driven intracellular pathways (Stevens et al 1999;Shi et al 2003). All this could be viewed as deeply conflicting with our results obtained in vivo.…”

“…Acute hyperglycemia in vitro downregulates TauT in cultured rat cardiomyocytes (Shi et al 2003), in cultured retinal pigment epithelial cells (Stevens et al 1999;Nakashima et al 2005) and in human Schwann cells (Askwith et al 2009). Glucose-induced TauT downregulation in human Schwann cells is reversed by inhibition of aldose reductase as well as by protein kinase C (PKC) inhibitors indicating the importance in the process of both osmolality (Askwith et al 2009) and of glucose-driven intracellular pathways (Stevens et al 1999;Shi et al 2003).…”

“…TauT is regulated by hypertonicity through the TonE (tonicity-responsive element)/TonB (TonE-binding protein) pathway (Uchida et al 1992;Han et al 2006;Ito et al 2004). Acute hyperglycaemia, moreover, reduces the expression of Taut mRNA and protein 'in vitro' in different cellular models (Stevens et al 1999;Askwith et al 2009) and, interestingly, oxidation, DNA damage, or dietary manipulation, also affect TauT expression (Matsell et al 1997;Han et al 2009;Han and Chesney 2010).…”

CD8+T Cell-Mediated Cytotoxicity toward Schwann Cells Promotes Diabetic Peripheral Neuropathy

“…Hyperglycemia not only potentially damages Schwann cells, but also induces the expression of inflammatory cytokines and chemokines in Schwann cells [13,23,24]. Here we found that high glucose levels induce very high levels of several leukocyte chemokines which are ligands for the T cell-specific chemokine receptor CXCR3 on Schwann cells (most notably CXCL9, CXCL10, and CXCL11), which might contribute to the infiltration of CD8 + T cells into DPN tissues.…”

Associations between Sensorimotor, Autonomic and Central Neuropathies in Diabetes Mellitus

“…The natural history of the disease varies from intermittent mild symptoms to manifest neuropathic pain, the latter being present in up to one fourth of the patients diminishing their quality of life [4][5][6]. The typical appearance is length dependent sensorimotor neuropathy caused by chronic progressive symmetric deafferentation and Schwann cell degeneration affecting axons of the distal lower extremities [2,7]. Sensorimotor neuropathy can be reliably assessed by use of vibration assessment, quantitative sensory testing measuring decreased sensitivity to pinprick and von Frey tactile detection threshold and electrophysiological techniques determining alterations of sensory nerve conduction velocity [8].…”