Prevention of hemodynamic and vascular albumin filtration changes in diabetic rats by aldose reductase inhibitors

Tilton, Ronald G.; Chang, Katherine; Pugliese, Giuseppe; Eades, Donald M; Province, Michael A.; Sherman, William R.; Kilo, Charles; Williamson, Joseph R.

doi:10.2337/diabetes.38.10.1258

Cited by 138 publications

(58 citation statements)

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“…Vascular dysfunction induced by diabetes includes hemodynamic changes and increased transvascular flux of macromolecules in both humans and animals, and numerous lines of evidence attest to a multifactorial pathogenesis (29). Results of our studies have linked increased flux of glucose via the sorbitol (polyol) pathway to vascular blood flow increases and hyperpermeability, because inhibitors of the two enzymes comprising this metabolic pathway block these vascular changes (39,40). Other mechanisms reported to have important roles in the pathogenesis of diabetic vascular dysfunction include increased diacylglycerol-protein kinase C activation (7,16), changes in intracellular NADH/NAD + coupled to oxidation of sorbitol to fructose in the second step of the sorbitol pathway (50), and increased formation of advanced glycation end products (4,5).…”

Section: Introductionmentioning

confidence: 81%

Vascular Dysfunction Induced by AGE is Mediated by VEGF via Mechanisms Involving Reactive Oxygen Species, Guanylate Cyclase, and Protein Kinase C

Ido

Chang

LeJeune³

et al. 2001

Microcirculation

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These observations indicate potentially important roles for oxygen free-radicals and nitric oxide in mediating permeability and blood flow changes induced by glycated proteins via mechanisms involving increased protein kinase C activity and VEGF production. Striking similarities in the mechanism by which hyperglycemia and glycated proteins induce vascular dysfunction suggest that a common pathway mediates effects of these different metabolic imbalances on vascular dysfunction.

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Section: Introductionmentioning

confidence: 81%

Vascular Dysfunction Induced by AGE is Mediated by VEGF via Mechanisms Involving Reactive Oxygen Species, Guanylate Cyclase, and Protein Kinase C

Ido

Chang

LeJeune³

et al. 2001

Microcirculation

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“…Bar, 0.5 gm any effect of aldose reductase inhibitors on increased mesangial fractional volume in diabetic rats [12], another study demonstrated that these drugs could prevent mesangial expansion in diabetic rats on a high protein diet [11]. Recently, Mauer et al reported that sorbinil can decrease GBM width in normal rats, although the mechanism is not known [8]. The disparity in effects of aldose reductase inhibitors in different tissues indicates that the polyol pathway may not be involved in the pathogenesis of GBM thickening in galactosaemic rats, even though it appears to have a role in the basement membrane thickening that occurs in the retinal and cerebral cortical capillaries of these animals.…”

Section: Labelling Densities Of Basement Membrane Componentsmentioning

confidence: 99%

“…The enzyme, aldose reductase has been immunocytochemically localized in glomerular podocytes [3] and cultured mesangial cells [4], and elevated concentrations of galactitol in the renal cortex of galactosaemic rats [5] and sorbitol in the renal papillae in diabetes [6] have been described. Although several investigators have shown that administration of aldose reductase inhibitors prevents renal hyperperfusion and increase in glomerular filtration rate in diabetic rats [7][8][9], one report failed to show such effect in these animals [10]. However, aldose reductase inhibition does not prevent glomerular basement membrane (GBM) thickening in diabetic rats [11][12][13].To examine further the relationship of the polyol pathway to diabetic nephropathy, we fed rats a diet containing 30% by weight galactose for nine months.…”

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confidence: 99%

Sorbinil does not prevent galactose-induced glomerular capillary basement membrane thickening in the rat

1990

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We investigated the role of the polyol pathway in the pathogenesis of glomerular basement membrane thickening in galactosaemic rats, an animal model that develops basement membrane lesions comparable to those of human diabetic subjects. Normotensive Wistar-Kyoto rats fed a 30% galactose diet for nine months developed significant glomerular basement membrane thickening by comparison with rats on a control test diet (p = 0.008). However, addition of an aldose reductase inhibitor, sorbinil (250 mg/kg diet), to the galactose diet did not prevent the increase in glomerular basement membrane thickness. Furthermore, by using a quantitative electron microscopic immunogold technique, we examined biochemical alterations in the composition of glomerular basement membranes in this animal model. The labelling density (comparable to relative concentration) of collagen type IV in thickened glomerular basement membranes of galactosaemic animals was significantly increased by comparison to those of control rats (p = 0.015). However, there was no significant difference in labelling densities of laminin and heparan sulfate proteoglycan core protein of these animals. Thus, our results indicate that an increase in glomerular basement membrane thickness accompanied by an increase in the labelling density of collagen type IV occurs in the galactosaemic rats, but this thickening is not prevented by sorbinil at the dose used in this experiment. Our study raises the strong possibility that glomerular basement membrane thickening in galactosaemic rats may not be due to excessive polyol pathway activity.

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“…Because of the localization and functions in the blood vessel, endothelial cells are considered candidates primarily involved in the pathogen-esis of diabetic vascular complications. Acute exposure to high glucose in nondiabetic individuals would induce vasodilation, owing to an increase of endothelium-derived nitric oxide (NO) formation [Tilton et al, 1989[Tilton et al, , 1992Sandeman et al, 1996;Houben et al, 1993;Williamson et al, 1993]. However, impairment of endothelium-dependent vascular relaxation in diabetic animals and humans has been shown [Durante et al, 1988;Tesfamariam et al, 1991;Tesfamariam, 1994].…”

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confidence: 99%

Nitric oxide prevents apoptosis of human endothelial cells from high glucose exposure during early stage

Liu

Liau

et al. 1999

J. Cell. Biochem.

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Hyperglycemia is a major cause of diabetic vascular disease. High glucose can induce reactive oxygen species (ROS) and nitric oxide (NO) generation, which can subsequently induce endothelial dysfunction. High glucose is also capable of triggering endothelial cell apoptosis. Little is known about the molecular mechanisms and the role of ROS and NO in high glucose-induced endothelial cell apoptosis. This study was designed to determine the involvement of ROS and NO in high glucose-induced endothelial cell apoptosis. Expression of endothelial nitric oxide synthase (eNOS) protein and apoptosis were studied in cultured human umbilical vein endothelial cells (HUVECs) exposed to control-level (5.5 mM) and high-level (33 mM) glucose at various periods (e.g., 2, 12, 24, 48 h). We also examined the effect of high glucose on H 2 O 2 production using flow cytometry. The results showed that eNOS protein expression was up-regulated by high glucose exposure for 2-6 h and gradually reduced after longer exposure in HUVECs. H 2 O 2 production and apoptosis, which can be reversed by vitamin C and NO donor (sodium nitroprusside), but enhanced by NOS inhibitor (N G -nitro-L-arginine methyl ether), were collated to a different time course (24-48 h) to HUVECs. These results provide the molecular basis for understanding that NO plays a protective role from apoptosis of HUVECs during the early stage (Ͻ24 h) of high glucose exposure, but in the late stage (Ͼ24 h), high glucose exposure leads to the imbalance of NO and ROS, resulting to the observed apoptosis. This may explain, at least in part, the impaired endothelial function and vascular complication of diabetic mellitus that would occur at late stages.

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Prevention of hemodynamic and vascular albumin filtration changes in diabetic rats by aldose reductase inhibitors

Cited by 138 publications

References 0 publications

Vascular Dysfunction Induced by AGE is Mediated by VEGF via Mechanisms Involving Reactive Oxygen Species, Guanylate Cyclase, and Protein Kinase C

Vascular Dysfunction Induced by AGE is Mediated by VEGF via Mechanisms Involving Reactive Oxygen Species, Guanylate Cyclase, and Protein Kinase C

Sorbinil does not prevent galactose-induced glomerular capillary basement membrane thickening in the rat

Nitric oxide prevents apoptosis of human endothelial cells from high glucose exposure during early stage

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