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  • 1
    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.
    Type of Medium: Electronic Resource
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  • 2
    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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  • 3
    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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