PPAR-alpha and -gamma agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse.
BACKGROUND
Peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonists are widely used in diabetes. In addition to their effects on lipid and glucose homeostasis, these agents have been postulated to have independent renoprotective actions. In the current study, we assess the efficacy of the PPAR-alpha agonist, gemfibrozil, the PPAR-gamma agonist rosiglitazone and the non-thiazolidinedione PPAR-alpha/gamma coagonist, compound 3q, on kidney structure and function in streptozotocin-treated apolipoprotein E knockout mice.


METHODS
Control and streptozotocin-diabetic mice were randomized to receive rosiglitazone (20 mg/kg/day), gemfibrozil (100 mg/kg/day), or compound 3q (3 mg/kg/day) by gavage, or no treatment for a period of 20 weeks. Renal fibrosis was assessed by standard histology and collagen IV immunohistochemistry. Kidney function was assessed by urinary albumin excretion and creatinine clearance.


RESULTS
Diabetes in this model was associated with an increase in glomerulosclerosis, tubulointerstitial fibrosis and increased collagen IV deposition in the glomeruli and tubules. All three agents significantly attenuated glomerulosclerosis, tubulointerstitial expansion and collagen IV deposition. The increase in albuminuria and the decline in kidney function associated with diabetes in this model were also attenuated by each of these agents, with no superiority observed among various treatment groups. These renoprotective effects were observed in the absence of changes in glucose, insulin or lipid levels or a reduction in blood pressure.


CONCLUSIONS
Combined with their independent anti-atherosclerotic actions, and their important effects on dyslipidaemia and insulin resistance, PPAR agonists may be useful for the prevention of diabetic complications, including kidney disease, even in type 1 diabetes.
Calkin
Anna C
AC
JDRF Danielle Alberti Memorial Centre for Diabetes complications, Baker Heart Research Institute, Melbourne, Australia. anna.calkin@baker.edu.au
Giunti
Sara
S
Jandeleit-Dahm
Karin A
KA
Allen
Terri J
TJ
Cooper
Mark E
ME
Thomas
Merlin C
MC
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015248:Gemfibrozil / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
D001057:Apolipoproteins E; D024141:Collagen Type IV; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D003404:Creatinine; D015248:Gemfibrozil