Diabetes-induced glomerular dysfunction: Links to a more reduced cytosolic ratio of NADH/NAD+

Tilton, Ronald G.; Baier, Lisa D.; Harlow, Judith E.; Smith, S. Ray; Ostrow, E; Williamson, Joseph R.

doi:10.1038/ki.1992.121

Cited by 106 publications

(62 citation statements)

References 53 publications

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“…This scenario is supported by evidence that: 1) VEGF expression is increased in cultured cells exposed to elevated glucose levels; 2) increased blood flow in granulation tissue induced by elevated glucose levels is prevented by polyclonal and monoclonal antibodies to VEGF. The role of each of the participants in this cascade is supported by evidence that increased blood flow induced by elevated glucose levels is also prevented by inhibitors of aldose reductase, sorbitol dehydrogenase, nitric oxide synthase, prostaglandin synthase, and superoxide dismutase [1][2][3][4]. Increased blood flow in soleus muscle of rats induced by acute hyperglycaemia is also prevented by superoxide dismutase.…”

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confidence: 75%

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Cytosolic NADH/NAD + , free radicals, and vascular dysfunction in early diabetes mellitus

1997

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confidence: 75%

“…In animal models of early diabetes the most important metabolic pathway contributing to cytosolic reductive stress appears to be increased flux of glucose via the sorbitol pathway [1][2][3][4]. In the first step of this pathway glucose is reduced to sorbitol by aldose reductase.…”

mentioning

confidence: 99%

Cytosolic NADH/NAD + , free radicals, and vascular dysfunction in early diabetes mellitus

1997

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“…While many metabolic imbalances associated with the diabetic milieu may generate excess reducing equivalents (12), the best characterized example is increased oxidation of sorbitol to fructose coupled to reduction of NAD ϩ to NADH by sorbitol dehydrogenase in the second step of the sorbitol pathway. This redox imbalance has been demonstrated in retina, kidney, and nerve (as well as in granulation tissue in this report) exposed to elevated glucose levels in vivo and in vitro, and has been linked to increased flux of glucose via the sorbitol pathway in each tissue (41)(42)(43). Furthermore, vascular dysfunction in each of these tissues in diabetic as well as in nondiabetic rats with acute hyperglycemia of 5 h duration (induced by i.v.…”

Section: Discussionmentioning

confidence: 97%

Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.

Tilton¹,

Kawamura²,

Chang³

et al. 1997

J. Clin. Invest.

175

143

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The purpose of these experiments was to investigate a potential role for vascular endothelial growth factor (VEGF) in mediating vascular dysfunction induced by increased glucose flux via the sorbitol pathway. Skin chambers were mounted on the backs of Sprague-Dawley rats and 1 wk later, granulation tissue in the chamber was exposed twice daily for 7 d to 5 mM glucose, 30 mM glucose, or 1 mM sorbitol in the presence and absence of neutralizing VEGF antibodies. Albumin permeation and blood flow were increased two-to three-fold by 30 mM glucose and 1 mM sorbitol; these increases were prevented by coadministration of neutralizing VEGF antibodies. Blood flow and albumin permeation were increased ‫ف‬ 2.5-fold 1 h after topical application of recombinant human VEGF and these effects were prevented by nitric oxide synthase (NOS) inhibitors (aminoguanidine and N G -monomethyl L -arginine). Topical application of a superoxide generating system increased albumin permeation and blood flow and these changes were markedly attenuated by VEGF antibody and NOS inhibitors. Application of sodium nitroprusside for 7 d or the single application of a calcium ionophore, A23187, mimicked effects of glucose, sorbitol, and VEGF on vascular dysfunction and the ionophore effect was prevented by coadministration of aminoguanidine. These observations suggest a potentially important role for VEGF in mediating vascular dysfunction induced by "hypoxia-like" cytosolic metabolic imbalances (reductive stress, increased superoxide, and nitric oxide production) linked to increased flux of glucose via the sorbitol pathway. ( J. Clin. Invest. 1997. 99:2192-2202.)

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“…The ARI, ponalrestat, only partially decreased kidney fructose in diabetic rats [50], and in isolated glomeruli exposed to a high glucose concentration, tolrestat suppressed sorbitol production without affecting fructose levels [51]. Deleterious changes in renal structure and function have been attributed to increased AGE formation in diabetes [52].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

et al. 1997

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Elevated polyol pathway activity has been implicated in the development of diabetic complications, including neuropathy [1]. In diabetic models, inhibitors of the first enzyme in the pathway, aldose reductase, prevent or correct nerve conduction velocity (NCV) and regeneration deficits [2][3][4][5][6][7][8][9][10][11][12][13]. Clinical trials of aldose reductase inhibitors (ARIs) have shown modest improvements in neurological symptoms, NCV, sensory measures, and an increase in nerve fibre regeneration [14-17] despite a less effective polyol pathway blockade than was found necessary for functional effects in animal studies [6,10,18].Several hypotheses have been advanced to explain the action of ARI. Some putative mechanisms are primarily dependent on the first half of the polyol pathway, conversion of glucose to sorbitol by aldose Diabetologia (1997) 40: 271-281 Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats Summary Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135 706, (250 mg ⋅ kg −1 ⋅ day −1 ) and an ARI, WAY-121 509, (10 mg ⋅ kg −1 ⋅ day −1 ) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6-8.2-fold) by WAY-135 706 whereas WAY-121 509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135 706 and WAY-121 509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9 %, respectively with diabetes. These deficits were corrected by WAY-121 509, but WAY-135 706 was completely ineffective. A 48.6 % diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121 509, but was unaltered by WAY-135 706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135 706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase. [Diabetologia (1997) 40: ...

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Diabetes-induced glomerular dysfunction: Links to a more reduced cytosolic ratio of NADH/NAD+

Cited by 106 publications

References 53 publications

Cytosolic NADH/NAD + , free radicals, and vascular dysfunction in early diabetes mellitus

Cytosolic NADH/NAD + , free radicals, and vascular dysfunction in early diabetes mellitus

Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

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