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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, Jharna Saha, MaryLee Schin, Jaeman Byun, Matthias Kretzler, Eva L.
Feldman, David A. Weild, Subramaniam Pennathur, Frank C. Brosius III
Frank Brosius on 3/28/2008
American journal of physiology. Renal physiology
Volume : Pages
295(4) : F1071 - F1081
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
University of Arizona
University of Michigan
University of Michigan
Neuropathy & Neurocognition
nephrosis 1 homolog, nephrin (human)
solute carrier family 1, member 3
solute carrier family 2 (facilitated glucose transporter), member 1
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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