In vivo biosynthesis and turnover of glomerular basement membrane in diabetic rats

Cohen, Morrel H.; Surma, Maria Linda; Wu, Van-Yu

doi:10.1152/ajprenal.1982.242.4.f385

Cited by 21 publications

(22 citation statements)

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“…Taken together, the data suggest that a decrease in the degradation of both type-IV collagen and fibronectin may contribute to the accumulation of these basement membrane components, under conditions of elevated D -glucose. The data support the hypothesis that decreased degradation of tubular basement membrane components may contribute to tubular basement membrane thickening in diabetic nephropathy, and is consistent with in vivo observations on the turnover of glomerular basement membrane in streptozotocin-induced diabetic rats [32]. …”

Section: Discussionsupporting

confidence: 90%

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

Phillips¹,

Morrisey²,

Steadman³

et al. 1999

Nephron Exp Nephrol

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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.

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Section: Discussionsupporting

confidence: 90%

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

Phillips¹,

Morrisey²,

Steadman³

et al. 1999

Nephron Exp Nephrol

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“…It has been reported that advanced glycation end products (AGEs), which are non-enzymatically glycated proteins, contribute to the pathogenesis of diabetic nephropathy and may be associated with the balance between turnover and degradation of ECM [6, 7, 8, 85, 86, 87, 88]. We have reported that a monoclonal anti-AGE antibody reacted with the mesangial area in patients with diabetic nephropathy and that the intensity of AGE staining gradually increased in parallel with the degree of mesangial expansion [7].…”

Section: Regulation Of Ecm Production and Degradation In Diabetic Nepmentioning

confidence: 99%

“…Moreover, we showed that a monoclonal antibody to reduced glycated lysine reacted with GBM in the glomeruli of diabetic nephropathy patients [8]. AGEs stimulate matrix production and inhibit mesangial proliferation [85]and glycated GBM is more resistant to digestion by protease [86]. Doi et al [87]showed that mouse mesangial cells exhibited an increase in mRNA and peptide synthesis of type IV collagen, laminin and heparan sulfate proteoglycan after exposure to AGEs.…”

Section: Regulation Of Ecm Production and Degradation In Diabetic Nepmentioning

confidence: 99%

Metalloproteinases in the Pathogenesis of Diabetic Nephropathy

Suzuki¹

1998

Nephron

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“…The pathogenesis of diabetic microangiopathy remains enigmatic, despite the acquisition of a great deal of knowledge concerning functional (1)(2)(3), biochemical (4), and morphological changes (5) in the vasculature of diabetic patients. These characteristic changes include increased regional vascular flow (1,2), increased microvascular permeability (3), capillary basement membrane thickening (4), and the presence of microaneurysms and neovascularization (5). It is likely that endothelial cells play an important role in the development of microangiopathy.…”

Section: Introductionmentioning

confidence: 99%

Identification of persistent defects in insulin receptor structure and function capillary endothelial cells from diabetic rats.

Kwok

Goldstein²,

Müller‐Wieland³

et al. 1989

J. Clin. Invest.

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Insulin actions and receptors were studied in capillary endothelial cells cultured from diabetic BB rats and their nondiabetic colony mates. The endothelial cells from diabetic rats of 2 mo duration had persistent biological and biochemical defects in culture. Compared with normal rats, endothelial cells from diabetic rats grew 44% more slowly. Binding studies of insulin and insulin-like growth factor I (IGF-I) showed that cells from diabetic rats had 50% decrease of insulin receptor binding (nondiabetic: 4.6±0.7; diabetic: 2.6±0.4% per milligram protein, P < 0.01), which was caused by a 50% decrease in the number of binding sites per milligram protein, whereas IGF-I binding was not changed. Insulin stimulation of 2-deoxy-glucose uptake and a-aminoisobutyric acid uptake were also severely impaired with a 80-90% decrease in maximal stimulation, in parallel with a 62% decrease of insulin-stimulated autophosphorylation (P < 0.05). 125I-insulin cross-linking revealed an 140-kD a subunit of the insulin receptor similar to that in cells from nondiabetic rats, although bands at > 200 kD were also detected. The molecular weight of the insulin receptor,8 subunit (by SDS-PAGE) was smaller in cells from diabetic than from normal rats (88-90 vs. 95 kD). Neuraminadase treatment of the partially purified insulin receptors decreased the molecular weight of the insulin receptors from nondiabetic rats to a greater degree than its diabetic counterpart. In contrast, Northern blot analysis of insulin receptor mRNAs using human cDNA probes revealed two species of 9.4 and 7.2 kb with no difference in mRNA abundance between cells from diabetic and nondiabetic rats. We conclude that the exposure of capillary endothelial cells to a diabetic milieu in vivo can cause specific and persistent changes in the insulin receptor and insulin action.

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In vivo biosynthesis and turnover of glomerular basement membrane in diabetic rats

Cited by 21 publications

References 0 publications

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

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

Metalloproteinases in the Pathogenesis of Diabetic Nephropathy

Identification of persistent defects in insulin receptor structure and function capillary endothelial cells from diabetic rats.

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