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Am J Physiol Renal Physiol (July 30, 2008). doi:10.1152/ajprenal.90208.2008
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Submitted on March 23, 2008
Revised on July 11, 2008
Accepted on July 28, 2008

Rosiglitazone Reduces Renal and Plasma Markers of Oxidative Injury and Reverses Urinary Metabolite Abnormalities in the Amelioration of Diabetic Nephropathy

Hongyu Zhang, Jharna Saha, Jaeman Byun, MaryLee Schin, Matthew Lorenz, Robert T. Kennedy1, Matthias Kretzler1, Eva L. Feldman2, Subramaniam Pennathur, and Frank C. Brosius III1*

1 University of Michigan
2 Univ. Michigan

* To whom correspondence should be addressed. E-mail: fbrosius{at}umich.edu.

Recent studies suggest that thiazolidinediones ameliorate diabetic nephropathy (DN) independent of their effect on hyperglycemia. In the current study we confirm and extend these findings by showing that rosiglitazone treatment prevented the development of DN and reversed multiple markers of oxidative injury in DBA/2J mice made diabetic by low dose streptozotocin. These diabetic mice developed a 14.2-fold increase in albuminuria and a 53% expansion of renal glomerular extracellular matrix after 12 weeks of diabetes. These changes were largely abrogated by administration of rosiglitazone beginning 2 weeks after the completion of streptozotocin injections. Rosiglitazone had no effect on glycemic control. Rosiglitazone had similar effects on insulin-treated diabetic mice after 24 weeks of diabetes. Podocyte loss and glomerular fibronectin accumulation, other markers of early DN, were prevented by rosiglitazone in both 12 and 24 week diabetic models. Surprisingly, glomerular GLUT1 levels did not increase and nephrin levels did not decrease in the diabetic animals; neither changed with rosiglitazone. Plasma and kidney markers of protein oxidation and lipid peroxidation were significantly elevated in the 24 week diabetic animals despite insulin treatment and were reduced to near normal levels by rosiglitazone. Finally, urinary metabolites were markedly altered by diabetes. Of 1988 metabolite features identified by Electrospray Ionization time of flight mass spectrometry, levels of 56 were altered > 2 fold in the urine of diabetic mice. Of these, 21 were returned to normal by rosiglitazone. Thus, rosiglitazone has direct effects on the renal glomerulus to reduce ROS accumulation to prevent type 1 diabetic mice from development of DN.




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