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1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 the Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA; the Children's Research Institute, the Children's Hospital of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: mliang{at}mcw.edu.
Pathological alterations in glomerular mesangial cells play a critical role in the development of diabetic nephropathy, the leading cause of end-stage renal disease. Molecular mechanisms mediating such alterations, however, remain to be fully understood. The present study first examined the effect of high glucose on the mRNA expression profile in rat mesangial cells using cDNA microarray. Based on variationweighted criteria and with a false discovery rate of 4.3%, 459 of 17,664 cDNA elements examined were found to be up-regulated and 151 down-regulated by exposure to 25 mM D-glucose for 5 days. A large number of differentially expressed genes belonged to several functional categories, indicating high glucose had a profound effect on mesangial cell proliferation, protein synthesis, energy metabolism, and, somewhat unexpectedly, protein sorting and the cytoskeleton. Interestingly, several thiol anti-oxidative genes (glutathione peroxidase 1, peroxiredoxin 6, and thioredoxin 2) were found by microarray and confirmed by real-time PCR to be up-regulated by high glucose. These changes suggested that the oxidative stress known to be induced in mesangial cells by high glucose might be buffered by up-regulation of the thiol anti-oxidative pathway. Upregulation of thiol anti-oxidative genes also occurred in high glucose-treated human mesangial cells and in glomeruli isolated from rats after one week of streptozotocininduced diabetes, but not in human proximal tubule cells. High glucose slightly increased lipid peroxidation and decreased the amount of reduced thiols in rat and human mesangial cells. Disruption of the thiol anti-oxidative pathway by two different thioloxidizing agents resulted in a 3-5 fold increase in high-glucose induced lipid peroxidation. In summary, the present study provided a global view of the short-term effect of high glucose on mesangial cells at the level of mRNA expression and identified the up-regulation of the thiol anti-oxidative pathway as an adaptational response of mesangial cells to high glucose.
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