Glomerular Polyol Accumulation in Diabetes and its Prevention by Oral Sorbinil

Beyer‐Mears, A.; Ku, Ling; Cohen, Morrel H.

doi:10.2337/diab.33.6.604

Cited by 116 publications

(28 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The result is an increase in tissue damage. The kidney is one of the target organs affected by oxidative stress in diabetes (Beyer-Mears et al, 1984;Bell et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress in hypopituitary dwarf mice and in transgenic mice overexpressing human and bovine GH

Carlson

Bharadwaj

Bartke

1999

AGE

View full text Add to dashboard Cite

Growth hormone (GH) stimulates metabolic activity. The purpose of this study was to examine whether it is involved in the aging process by increasing oxidative stress. Inorganic peroxides and lipid peroxides were measured in kidney and liver samples in dwarf mice that are deficient in GH, prolactin and thyrotropin and in transgenic mice that produce high levels of GH. In normal male mice, there was an increase in inorganic peroxides in the kidney with age. Levels were lower in old male dwarfs when compared with normal male mice of similar age. Unexpectedly, concentrations of inorganic peroxides were frequently lower in transgenic male and female mice expressing extra copies of GH than in normal controls. Lipid peroxide concentrations were more variable. Transgenic animals expressing bovine GH had the highest levels of lipid peroxides. In dwarfs, kidney levels were similar to those of normal mice but concentrations in the liver were more variable. This study does not indicate that the decrease in life span in transgenic mice producing high levels of GH is due to an increase of oxidative stress. Rather, it suggests that expression of extra copies of the GH gene may lead to a compensatory increase in antioxidant protection.

show abstract

“…The result is an increase in tissue damage. The kidney is one of the target organs affected by oxidative stress in diabetes (Beyer-Mears et al, 1984;Bell et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress in hypopituitary dwarf mice and in transgenic mice overexpressing human and bovine GH

Carlson

Bharadwaj

Bartke

1999

AGE

View full text Add to dashboard Cite

show abstract

“…The enzymes of the polyol pathway, aldose reductase and sorbitol dehydrogenase, have been identified in glomerular cells including mesangial cells [26]. Furthermore, sorbitol accumulation has been found in glomeruli isolated from streptozotocin (STZ)-diabetic rats, and this change is considered to result in the myoinositol depletion and subsequent impairment of Na/K-ATPase activity found in diabetic glomeruli [27,28]. It is observed that a high-glucose condition per se is able to cause sorbitol accumulation and myoinositol depletion in cultured rat mesangial cells [29].…”

Section: Activation Of the Polyol Pathwaymentioning

confidence: 98%

Mesangial Cell Dysfunction as a Pathogenesis of Diabetic Nephropathy

Haneda¹,

Koya²,

Kikkawa³

2001

Contributions to Nephrology

View full text Add to dashboard Cite

Clinical studies, such as the Diabetes Control and Complications Trial (DCCT) in subjects with type-1 diabetes [1] and the UK Prospective Diabetes Study (UKPDS) in subjects with type-2 diabetes [2], clearly link hyperglycemia to diabetic nephropathy. Furthermore, the maintenance of normoglycemia for 10 years by pancreatic transplantation reduced glomerular pathological changes in 8 subjects with type-1 diabetes [3]. Therefore, the understanding of the hyperglycemia-related molecular pathogenesis of diabetic nephropathy is truly needed to provide a further insight into therapeutic strategies for diabetic nephropathy.Diabetic nephropathy is characterized histologically by an accumulation of extracellular matrix (ECM) proteins in the glomerular mesangium [4,5]. Functionally, an increase in glomerular filtration rates, glomerular hyperfiltration, found in the early phase of diabetes has been proposed to be related to the future development of diabetic nephropathy [6,7]. These abnormalities could be caused by functional changes in the diabetic glomeruli, particularly in glomerular mesangial cells, because mesangial cells were found to be capable of producing ECM proteins [8,9] and regulating glomerular filtration rates through their contractility [10,11]. An enhancement of the production of type-IV collagen and fibronectin [12][13][14], a reduction in the contractile responsiveness to angiotensin II (ANG II) [15][16][17] and an overproduction of vasorelaxing eicosanoids [18][19][20] have been shown in diabetic glomeruli and mesangial cells cultured under high-glucose conditions. These functional changes in glomeruli and mesangial cells in diabetes are thought to be caused by metabolic abnormalities in the glomeruli and mesangial cells specific to diabetes. In this review, the relationship between the metabolic abnormalities and the functional disturbance of mesangial cells in the diabetic milieu is described with a special Downloaded by: Fudan University Library 61.129.42.15 -5/15/2015 6:44:27 AM

show abstract

“…A common mechanism by which glucose modulates cell function is by increased polyol pathway activity [33, 34, 35]. Metabolism of glucose by the polyol pathway consists of two reactions (fig.…”

Section: Discussionmentioning

confidence: 99%

Decreased Degradation of Collagen and Fibronectin following Exposure of Proximal Cells to Glucose

Phillips¹,

Morrisey²,

Steadman³

et al. 1999

Nephron Exp Nephrol

View full text Add to dashboard Cite

Background/Aims: Thickening and reduplication of the tubular basement membrane has been reported as an early event in diabetic nephropathy. The aim of the work outlined here was to examine the effects and mechanisms involved in the modulation of renal proximal tubular type-IV collagen and fibronectin turnover by glucose. Methods: The effect of glucose on type-IV collagen and fibronectin generation was studied by exposure of primary cultures of human renal proximal tubular cells (HPTC) to elevated D-glucose concentrations. Subsequently the mechanism of modulation of fibronectin generation was examined in a polarised system utilising the porcine proximal tubular cell line LLC-PK1 grown on porous tissue culture inserts. Results: Incubation of confluent growth-arrested HPTC with 25 mM D-glucose led to the accumulation of both type-IV collagen and fibronectin. This increase was not dependent on new gene transcription for either protein. Exposure of HPTC to 25 mM D-glucose also led to the induction of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and also gelatinase A. There was, however, a net decrease in overall gelatinolytic activity. Incubation of confluent monolayers of LLC-PK1 cells grown on tissue culture inserts with 25 mM D-glucose on either their apical or basolateral aspect led to fibronectin accumulation seen only in the basolateral compartment. Under these experimental conditions, we can demonstrate polyol pathway activation, and furthermore the increase in fibronectin concentration in response to glucose was inhibited by the aldose reductase inhibitor sorbinil. Fibronectin accumulation was also demonstrated following both apical and basolateral addition of 1 mM sorbitol, but not following the addition of 25 mM galactose to either aspect of the cells. Conclusions: These data demonstrate that the glucose-induced accumulation of type-IV collagen and fibronectin was associated with alterations in the degradative pathway of these matrix components. In addition fibronectin generation in response to glucose was non-polar in terms of application of glucose, but polar in terms of fibronectin accumulation. The mechanisms of glucose-induced modulation of fibronectin were mediated by polyol pathway activation, and more specifically related to the metabolism of sorbitol to fructose.

show abstract

Glomerular Polyol Accumulation in Diabetes and its Prevention by Oral Sorbinil

Cited by 116 publications

References 7 publications

Oxidative stress in hypopituitary dwarf mice and in transgenic mice overexpressing human and bovine GH

Oxidative stress in hypopituitary dwarf mice and in transgenic mice overexpressing human and bovine GH

Mesangial Cell Dysfunction as a Pathogenesis of Diabetic Nephropathy

Decreased Degradation of Collagen and Fibronectin following Exposure of Proximal Cells to Glucose

Contact Info

Product

Resources

About