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Am J Physiol Renal Physiol 295: F1071-F1081, 2008. First published July 30, 2008; doi:10.1152/ajprenal.90208.2008
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Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy

Hongyu Zhang,1 Jharna Saha,1 Jaeman Byun,1 MaryLee Schin,1 Matthew Lorenz,4 Robert T. Kennedy,4,5 Matthias Kretzler,1 Eva L. Feldman,2 Subramaniam Pennathur,1 and Frank C. Brosius, III1,3

Departments of 1Internal Medicine, 2Neurology, 3Molecular and Integrative Physiology, 4Chemistry, and 5Pharmacology, University of Michigan, Ann Arbor, Michigan

Submitted 23 March 2008 ; accepted in final form 28 July 2008

Recent studies suggest that thiazolidinediones ameliorate diabetic nephropathy (DN) independently 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 wk of diabetes. These changes were largely abrogated by administration of rosiglitazone beginning 2 wk after the completion of streptozotocin injections. Rosiglitazone had no effect on glycemic control. Rosiglitazone had similar effects on insulin-treated diabetic mice after 24 wk of diabetes. Podocyte loss and glomerular fibronectin accumulation, other markers of early DN, were prevented by rosiglitazone in both 12- and 24-wk 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-wk diabetic animals despite insulin treatment and were reduced to near-normal levels by rosiglitazone. Finally, urinary metabolites were markedly altered by diabetes. Of 1,988 metabolite features identified by electrospray ionization time of flight mass spectrometry, levels of 56 were altered more than twofold 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 reactive oxygen species accumulation to prevent type 1 diabetic mice from development of DN.

diabetes; thiazolidinedione; kidney; complications; metabolomics; mass spectrometry


Address for reprint requests and other correspondence: F. C. Brosius, Univ. of Michigan, 5520 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5680 (e-mail: fbrosius{at}umich.edu)




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