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  • 1
    ISSN: 1432-0428
    Keywords: Key words: Hyaluronan ; prostaglandin ; sulphated proteoglycan ; glycosaminoglycan ; mesangial cell.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Exposure in vivo or in vitro to elevated glucose increases production of vasoactive prostaglandins by glomeruli and mesangial cells. This study aimed to determine whether this increased prostaglandin production could provide a link with later structural changes in diabetic nephropathy. Glomerular cores were prepared from control rats and streptozotocin-diabetic rats (3 weeks' duration). Over 24 h in culture hyaluronan production from diabetic glomerular cores was higher than production from control glomerular cores whether maintained in 5.6 mmol/l glucose (105.6 ± 15.5 vs 53.6 ± 8.5 ng hyaluronan per 250 glomerular cores, p 〈 0.001); in 25 mmol/l glucose (149.3 ± 34.8 vs 62.7 ± 7.8 ng hyaluronan per 250 glomerular cores, p 〈 0.01); or in 45 mmol/l glucose (176.8 ± 23.3 vs 102.0 ± 17.9 ng hyaluronan per 250 glomerular cores, p 〈 0.01). At 5.6 mmol/l glucose, exposure in vitro to prostaglandin E2 caused an increase in hyaluronan production [maximal at 10 − 9 mol/l prostaglandin E2, 237 ± 19 vs 42 ± 4, ng hyaluronan per 250 glomerular cores, p 〈 0.001 (control) and 195 ± 7 vs 103 ± 5, ng hyaluronan per 250 glomerular cores, p 〈 0.001 (diabetic) ]. In both control and diabetic glomerular cores hyaluronan production was reduced significantly by the cyclooxygenase inhibitor indomethacin (10−5 mol/l) [24.7 ± 3.33 vs 40.25 ± 4.11 ng hyaluronan per 250 glomerular cores, p 〈 0.05 (control) and 36.5 ± 6.25 vs 118.0 ± 22.6, p 〈 0.01 (diabetic) ]. A direct spectrophotometric microassay was used to determine the concentration of sulphated glycosaminoglycans derived from papain-digested glomerular core proteoglycans. Release of sulphated glycosaminoglycans from diabetic glomerular cores maintained at 5.6 mmol/l glucose was decreased [41.9 ± 1.1 vs 54.0 ± 1.0 μg of sulphated glycosaminoglycans (chondroitin sulphate) per 250 glomerular cores p 〈 0.01]. A decrease in sulphated glycosaminoglycans was also shown from control glomerular cores maintained at 25 mmol/l glucose. At this glucose concentration, addition of exogenous hyaluronan or prostaglandin E2 significantly reduced sulphated glycosaminoglycans from control and diabetic glomerular cores. It is concluded that increased prostaglandin production secondary to high glucose environment can lead to an increased glomerular hyaluronan synthesis. This can substantially affect the levels of sulphated glycosaminoglycans in the extracellular matrix. We propose that these effects provide a possible link between the initial biochemical consequences of hyperglycaemia and later structural changes seen in the glomerulus in diabetes. [Diabetologia (1995) 38: 298–305]
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  • 2
    ISSN: 1432-0428
    Keywords: Diabetic nephropathy ; albuminuria ; aldose reductase inhibitors ; prostaglandins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of two structurally unrelated aldose reductase inhibitors, sorbinil and ponalrestat, on glomerular prostaglandin production and urinary albumin excretion was investigated in rats with diabetes induced by streptozotocin. It was found that both aldose reductase inhibitors, when administered from the time of induction of the diabetes, significantly decreased the raised urinary albumin excretion in the diabetic rats, although it remained elevated compared with non-diabetic rats. Glomerular prostaglandin E and 6-ketoprostaglandin F1α production was significantly increased in glomeruli obtained from the diabetic rats. Inhibition of aldose reductase caused a reduction in the raised glomerular prostaglandin production, although this remained above that observed in the non-diabetic rats. Subsequent experiments were performed to determine whether the effects of the aldose reductase inhibitors could be explained by effects on glomerular filtration rate. It was found that ponalrestat, at a dose which markedly reduced urinary albumin excretion, did not significantly affect glomerular filtration rate in non-diabetic rats, rats with untreated streptozotocin-induced diabetes and rats with diabetes partially treated with low dose insulin. Glomerular sorbitol concentrations were significantly elevated in untreated diabetic rats as early as two weeks after the induction of diabetes. It is concluded that the administration of aldose reductase inhibitors from the time of induction of diabetes significantly reduces glomerular prostaglandin production and urinary albumin excretion. The latter effect is not due to an effect on glomerular filtration rate. Increased polyol pathway activity may account in part for the increased glomerular prostaglandin production and urinary albumin excretion in early experimental diabetes.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 35 (1992), S. 499-504 
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A large number of experimental studies in animals and retrospective or non-randomised prospective studies in humans provide support for the concept that the microvascular complications of diabetes mellitus are dependent on hyperglycaemia. This review focuses on four potential bio-chemical pathways linking hyperglycaemia to changes within the kidney which can plausibly be linked to the functional and structural changes characterising diabetic nephropathy. These four pathways are the polyol pathway, non-enzymatic glycation, glucose autoxidation and de novo synthesis of diacylglycerol leading to protein kinase C and phospholipase A2 activation. Rather than being independent, there are several potential interactions between these four pathways which may explain confusing and overlapping effects observed in studies examining inhibitors of individual pathways. As many of the steps which follow on glucose metabolism are subject to modification by dietary and pharmacological means, the further delineation of the pathogenetic sequence leading to tissue damage in diabetes should allow a logical and effective approach to the prevention or treatment of the complications of diabetes.
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  • 4
    ISSN: 1432-0428
    Keywords: Diabetes mellitus ; focal adhesion kinase ; glomeruli ; prostaglandins ; fibronectin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Altered extracellular matrix production by the glomerular mesangium is a feature of diabetes mellitus. Matrix proteins, including fibronectin, via interaction with cell-surface receptors (the integrins) may activate intracellular pathways such as prostaglandin production, shown previously to be stimulated by addition of fibronectin to glomerular cores. However, the signalling pathways involved are unclear. An intracellular tyrosine kinase (focal adhesion kinase), associated with focal adhesions, is known to be phosphorylated after interaction with matrix proteins. We now show for the first time, in glomeruli from diabetic rats, that focal adhesion kinase has increased phosphorylation on tyrosine, when compared with non-diabetic control rats. This phosphorylation was labile and disappeared with extended time of sample preparation or digestion of glomeruli to glomerular cores. Cultured mesangial cells, from non-diabetic rats, plated onto fibronectin also showed increased tyrosine phosphorylation of focal adhesion kinase accompanied by a twofold increase in prostaglandin production. However, it may not be possible to replicate fully the diabetic “state” in vitro merely by use of raised glucose concentrations, as these conditions (for 3 weeks) resulted in decreased focal adhesion kinase phosphorylation, despite increased fibronectin and prostaglandin levels. A role for increased focal adhesion kinase phosphorylation in kidney glomeruli isolated from diabetic rats, and any linkage to intracellular signalling pathways remains to be determined.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Hyaluronan ; prostaglandin ; sulphated proteoglycan ; glycosaminoglycan ; mesangial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Exposure in vivo or in vitro to elevated glucose increases production of vasoactive prostaglandins by glomeruli and mesangial cells. This study aimed to determine whether this increased prostaglandin production could provide a link with later structural changes in diabetic nephropathy. Glomerular cores were prepared from control rats and streptozotocin-diabetic rats (3 weeks' duration). Over 24 h in culture hyaluronan production from diabetic glomerular cores was higher than production from control glomerular cores whether maintained in 5.6 mmol/l glucose (105.6±15.5 vs 53.6±8.5 ng hyaluronan per 250 glomerular cores, p〈0.001); in 25 mmol/l glucose (149.3±34.8 vs 62.7±7.8 ng hyaluronan per 250 glomerular cores, p〈0.01); or in 45 mmol/l glucose (176.8±23.3 vs 102.0±17.9 ng hyaluronan per 250 glomerular cores, p〈0.01). At 5.6 mmol/l glucose, exposure in vitro to prostaglandin E2 caused an increase in hyaluronan production [maximal at 10−9 mol/l prostaglandin E2, 237±19 vs 42±4, ng hyaluronan per 250 glomerular cores, p〈0.001 (control) and 195±7 vs 103±5, ng hyaluronan per 250 glomerular cores, p〈0.001 (diabetic)]. In both control and diabetic glomerular cores hyaluronan production was reduced significantly by the cyclooxygenase inhibitor indomethacin (10−5 mol/l) [24.7±3.33 vs 40.25±4.11 ng hyaluronan per 250 glomerular cores, p〈0.05 (control) and 36.5±6.25 vs 118.0±22.6, p〈0.01 (diabetic)]. A direct spectrophotometric microassay was used to determine the concentration of sulphated glycosaminoglycans derived from papain-digested glomerular core proteoglycans. Release of sulphated glycosaminoglycans from diabetic glomerular cores maintained at 5.6 mmol/l glucose was decreased [41.9±1.1 vs 54.0±1.0 Μg of sulphated glycosaminoglycans (chondroitin sulphate) per 250 glomerular cores p〈0.01]. A decrease in sulphated glycosaminoglycans was also shown from control glomerular cores maintained at 25 mmol/l glucose. At this glucose concentration, addition of exogenous hyaluronan or prostaglandin E2 significantly reduced sulphated glycosaminoglycans from control and diabetic glomerular cores. It is concluded that increased prostaglandin production secondary to high glucose environment can lead to an increased glomerular hyaluronan synthesis. This can substantially affect the levels of sulphated glycosaminoglycans in the extracellular matrix. We propose that these effects provide a possible link between the initial biochemical consequences of hyperglycaemia and later structural changes seen in the glomerulus in diabetes.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Key words Diabetes mellitus ; focal adhesion kinase ; glomeruli ; prostaglandins ; fibronectin.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Altered extracellular matrix production by the glomerular mesangium is a feature of diabetes mellitus. Matrix proteins, including fibronectin, via interaction with cell-surface receptors (the integrins) may activate intracellular pathways such as prostaglandin production, shown previously to be stimulated by addition of fibronectin to glomerular cores. However, the signalling pathways involved are unclear. An intracellular tyrosine kinase (focal adhesion kinase), associated with focal adhesions, is known to be phosphorylated after interaction with matrix proteins. We now show for the first time, in glomeruli from diabetic rats, that focal adhesion kinase has increased phosphorylation on tyrosine, when compared with non-diabetic control rats. This phosphorylation was labile and disappeared with extended time of sample preparation or digestion of glomeruli to glomerular cores. Cultured mesangial cells, from non-diabetic rats, plated onto fibronectin also showed increased tyrosine phosphorylation of focal adhesion kinase accompanied by a twofold increase in prostaglandin production. However, it may not be possible to replicate fully the diabetic “state” in vitro merely by use of raised glucose concentrations, as these conditions (for 3 weeks) resulted in decreased focal adhesion kinase phosphorylation, despite increased fibronectin and prostaglandin levels. A role for increased focal adhesion kinase phosphorylation in kidney glomeruli isolated from diabetic rats, and any linkage to intracellular signalling pathways remains to be determined. [Diabetologia (1995) 38: 1131–1137]
    Type of Medium: Electronic Resource
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