Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy.
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.
Zhang
Hongyu
H
Department of Internal Medicine, University of Michigan, 5520 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5680, USA.
Saha
Jharna
J
Byun
Jaeman
J
Schin
MaryLee
M
Lorenz
Matthew
M
Kennedy
Robert T
RT
Kretzler
Matthias
M
Feldman
Eva L
EL
Pennathur
Subramaniam
S
Brosius
Frank C
FC
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D050199:Podocytes / Q000473:pathology; D000077154:Rosiglitazone; D021241:Spectrometry, Mass, Electrospray Ionization; D045162:Thiazolidinediones / Q000494:pharmacology*; D014556:Urine
D015415:Biomarkers; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone