Protective effect of d-α-tocopherol on the function of human mesangial cells exposed to high glucose concentrations

Tada, Hayato; Ishii, H.; Isogai, Sho

doi:10.1016/s0026-0495(97)90122-0

Cited by 42 publications

(18 citation statements)

References 35 publications

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“…Although additional PKC isoforms may be translocated and modulated independently of one another in this particular model (27) cate these isozymes in initiating diabetic complications (8,26). With respect to nitecapone-treated diabetic rats, a normalization of glomerular PKC activation was noted, which is consistent with a potential antioxidant-dependent mechanism of PKC inhibition (9,29,35). The common pathway by which different antioxidants act to prevent PKC activation in diabetes has not been clearly defined, but it is speculated that they exert their neutralizing effect either by interfering with diacylglycerol metabolism (29) or by disrupting the ability of diacylglycerol to interact with and activate PKC (9).…”

Section: Discussionmentioning

confidence: 53%

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

et al. 2000

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The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopaminemetabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopaminedependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,KATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMTinhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy. Diabetes 49:1381-1389, 2000

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Section: Discussionmentioning

confidence: 53%

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

et al. 2000

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“…Moreover, D-a-tocopherol treatment reduced high glucose-induced eicosanoid and fibronectin production in mesangial cells, together with increased DAG concentrations and PKC activity [113].…”

Section: Mediators Of Hyperglycaemia-induced Injurymentioning

confidence: 91%

15 th Golgi lecture: from hyperglycaemia to the dysregulation of vascular remodelling in diabetes

Mario

Pugliese

2001

Diabetologia

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Hyperglycaemia has been shown to play a central part in diabetic vascular disease, which is also influenced by individual background. Hyperglycaemia initiates the pathogenetic sequence through a series of interrelated biochemical abnormalities, including increased flux through the polyol and hexosamine pathways, oxidative stress, AGE formation and protein kinase C activation. These abnormalities are capable of modifying the function of resident and non-resident vascular cells by changing their production pattern of several autocrine and paracrine factors, including growth, vasoactive and coagulation factors and adhesion molecules. These mediators profoundly impair the physiologic turnover of the vessel wall, thus leading to an abnormal process of vascular remodelling, with alterations in cell and matrix turnover and contacts, vascular tone and permeability and coagulation pattern. This process has distinct features depending on the target tissue. The hallmark of nephropathy is an abnormal accumulation of extracellular matrix within the mesangium, sustained by an upregulation of TGF-b, possibly triggered by a local activation of the renin-angiotensin system. The central pathological lesion in retinopathy is retinal ischaemia due to the formation of acellular capillaries. The resulting vascular endothelial growth factor-dependent neovascularization is a detrimental phenomenon leading to the formation of noncompetent vessels. Conversely, in macrovascular disease, arterial occlusion resulting from plaque formation with superimposed thrombosis elicits an angiogenic response which is impaired, but generates competent vessels, potentially compensating for reduced flow. Thus, upstream interventions interrupting the pathogenetic sequence at the level of hyperglycaemia (and related biochemical events) are the most effective, whereas downstream interventions should be targeted to the tissue affected. [Diabetologia (2001) 44: 674±692]

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“…Human MCs were cultured as previously reported [5]. A single cell line between the third and eighth passages was employed in this study.…”

Section: Methodsmentioning

confidence: 99%

An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-? and protein kinase C activity in cultured human mesangial cells

1998

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Diabetic nephropathy is a leading cause of morbidity and mortality in diabetes mellitus. Since diabetic glomerulopathy is characterized by an expansion of glomerular mesangium that eventually progresses to obliterate the capillary lumen, mesangial cells (MCs) are thought to play a central role in the pathogenesis of diabetic nephropathy. Elevated glucose levels appear to initiate MC dysfunction, probably via metabolic abnormalities such as derangements in polyol pathway [1], increased activity of protein kinase C (PKC) [2,3], and increased production of transforming growth factor-b (TGF-b) [4]. However, the interaction between these metabolic abnormalities is unclear. To clarify this, we investigated whether inhibition of the polyol pathway by an aldose reductase inhibitor (ARI) could prevent the glucose-induced increase in the production of TGF-b and the activity of PKC in cultured human MCs. Materials and methodsHuman MCs were cultured as previously reported [5]. A single cell line between the third and eighth passages was employed in this study. RPMI-1640 medium (GIBCO BRL, Gaithersburg, Md., USA) containing 20 % fetal calf serum (FCS) was supplemented with either 5 or 33 mmol/l glucose in the presence (10 ±8~5 10 ±5 mol/l) or absence of epalrestat. Medium supplemented with 5 mmol/l glucose + 28 mmol/l mannitol was used as an osmotic control. Since our preliminary experiments showed that incubating MCs with 33 mmol/l glucose for 6 days resulted in a greater increase in TGF-b proDiabetologia (1998) 41: 362±364 Rapid communicationAn aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-b and protein kinase C activity in cultured human mesangial cells Summary We investigated the effect of inhibition of a polyol pathway on the glucose-induced increase in transforming growth factor-b (TGF-b) production and activity of protein kinase C (PKC) in cultured human mesangial cells (MCs). The exposure of MCs to 33 mmol/l glucose resulted in an increase in TGF-b production, measured by ELISA, compared with 5 mmol/l glucose. The glucose-induced increase in TGF-b was prevented by concomitant incubation with epalrestat, an aldose reductase inhibitor (ARI), in a dose-dependent manner at a concentration of more than 10 ±6 mol/l. Moreover, the glucose-induced enhancement of PKC activity in the membrane fraction of MCs was also abolished by epalrestat. The addition of epalrestat to MCs cultured with 5 mmol/l glucose showed no demonstrable effects on TGF-b production and PKC activity. These results provide direct evidence for linkages between derangements in polyol pathway and glucose-induced overproduction of TGF-b and enhancement of PKC activity in MCs. Accordingly, the effect of an ARI on these metabolic abnormalities in MCs may justify its clinical application for treatment of diabetic nephropathy.[ Diabetologia (1998) 41: 362±364]

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Protective effect of d-α-tocopherol on the function of human mesangial cells exposed to high glucose concentrations

Cited by 42 publications

References 35 publications

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

15 th Golgi lecture: from hyperglycaemia to the dysregulation of vascular remodelling in diabetes

An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-? and protein kinase C activity in cultured human mesangial cells

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