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Publication

Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy

Authors Hongyu Zhang, Jharna Saha, MaryLee Schin, Jaeman Byun, Matthias Kretzler, Eva L. Feldman, David A. Weild, Subramaniam Pennathur, Frank C. Brosius III Submitted By Frank Brosius on 3/28/2008 Status Published Journal American journal of physiology. Renal physiology Year 2008 Date Published 10/1/2008 Volume : Pages 295(4) : F1071 - F1081 PubMed Reference 18667486 Abstract 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 substantially 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 3602 metabolite features identified by Electrospray Ionization, levels of 166 were altered > 2 fold in the urine of diabetic mice. Of these, 75 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.

Investigators with authorship
Name Institution Frank Brosius University of Arizona Eva Feldman University of Michigan Matthias Kretzler University of Michigan

Complications
All ComplicationsBioinformatics BoneCardiomyopathy CardiovascularGastro-Intestinal (GI) NephropathyNeuropathy & Neurocognition Pediatric Endocrinology Retinopathy UropathyWound Healing

Genes
Symbol Description Nphs1 nephrosis 1 homolog, nephrin (human) Slc1a3 solute carrier family 1, member 3 Slc2a1 solute carrier family 2 (facilitated glucose transporter), member 1