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      Interaction between the Polyol Pathway and Non-Enzymatic Glycation on Mesangial Cell Gene Expression

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          Background/Aims: Both activation of the polyol pathway and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic glomerulopathy. We investigated the interaction between these two pathways using normal mesangial cells (MCs) and transgenic (TG) MCs with elevated aldose reductase (AR) activity. Methods: TG mice with expression of the human AR (hAR) gene in kidney MCs were established. Mouse glomeruli and primary cultures of MCs from hAR TG and wild-type (WT) mice were studied regarding the changes in AR activity, transforming growth factor-β<sub>1</sub> (TGF-β<sub>1</sub>) and type IV collagen mRNA and protein levels, in response to BSA modified by advanced glycation end-products (AGE-BSA). Results: Ex vivo addition of AGE-BSA increased AR activity, TGF-β<sub>1</sub> and type IV collagen mRNA levels in both WT and TG glomeruli, with greater rise in TG glomeruli. These increments were attenuated by zopolrestat, an AR inhibitor. In cultured MCs, AGE-BSA enhanced AR activity, TGF-β<sub>1</sub> and type IV collagen mRNA and protein levels both in WT and TG MCs, again with greater increases in TG MCs. The AGE-induced enhancement in TGF-β<sub>1</sub> and type IV collagen expression were suppressed by either zopolrestat or transfection with an AR antisense oligonucleotide. Conclusion: These data suggest that the activation of the polyol pathway by AGEs, more marked in genetic conditions with increased AR activity, may contribute to the pathogenesis of diabetic glomerulopathy, through enhancing mesangial cell expression of TGF-β<sub>1</sub> and type IV collagen.

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          Most cited references 24

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          Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens.

          Aldose reductase (AR) has been implicated in the etiology of diabetic cataract, as well as in other complications. However, the role of AR in these complications remains controversial because the strongest supporting evidence is drawn from the use of AR inhibitors for which specificity in vivo cannot be ascertained. To settle this issue we developed transgenic mice that overexpress AR in their lens epithelial cells and found that they become susceptible to the development of diabetic and galactose cataracts. When the sorbitol dehydrogenase-deficient mutation is also present in these transgenic mice, greater accumulation of sorbitol and further acceleration of diabetic cataract develop. These genetic studies demonstrated convincingly that accumulation of polyols from the reduction of hexose by AR leads to the formation of sugar cataracts.
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            Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease.

            Several lines of evidence suggest that the excessive accumulation of extracellular matrix in the glomeruli of diabetic kidneys may be due to reactive intermediates forming between glucose and matrix proteins called advanced glycation end products (AGEs). Normal mice received AGE-modified mouse serum albumin i.p. for 4 weeks, and glomerular extracellular matrix, growth factor mRNA levels, and morphology were examined. We found that AGE induced an increase in glomerular extracellular matrix alpha 1(IV) collagen, laminin B1, and transforming growth factor beta 1 mRNA levels, as measured by competitive PCR, as well as glomerular hypertrophy. The AGE response was specific because the coadministration of an AGE inhibitor, aminoguanidine, reduced all these changes. We conclude that AGEs affected expression of genes implicated in diabetic kidney disease and may play a major role in nephropathy.
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              Glomerular epithelial, mesangial, and endothelial cell lines from transgenic mice.

              The culture of glomerular cells has represented an important tool in the understanding of individual glomerular cell functions. However, the complexity of the glomerulus has made it difficult to obtain pure cell populations. It has also been difficult to culture glomerular endothelial cells, even as mixed cell populations. At present there are no established glomerular cell lines from any source. We have established permanent cell lines of cloned glomerular epithelial, mesangial, and endothelial cells from a line of mice transgenic for the early region of simian virus 40 (SV40). These mice appear normal at birth but by three to four months of age have sclerosis affecting a variable percentage of their glomeruli. The cells maintain features characteristic of their normal counterparts despite their transformed phenotype. These cell lines could be useful tools in understanding the pathogenesis of glomerulosclerosis in this transgenic mouse model and in studying those features of normal glomerular cell biology which are not altered by a transformed phenotype.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                November 2004
                17 November 2004
                : 98
                : 3
                : e89-e99
                aDepartment of Medicine and bInstitute of Molecular Biology, The University of Hong Kong, Hong Kong, PR China
                80684 Nephron Exp Nephrol 2004;98:e89–e99
                © 2004 S. Karger AG, Basel

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                Figures: 6, References: 31, Pages: 1
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