Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha.
Peroxisome proliferator-activated receptor (PPAR)alpha, a member of the ligand-activated nuclear receptor superfamily, plays an important role in lipid metabolism and glucose homeostasis and is highly expressed in the kidney. The present studies were aimed at determining the role of PPARalpha in the pathogenesis of diabetic nephropathy using PPARalpha-knockout mice and cultured murine mesangial cells. Diabetes was induced using a low-dose streptozotocin protocol in 8-week-old male 129 SvJ PPARalpha-knockout and wild-type mice. Diabetic PPARalpha-knockout and wild-type mice developed elevated fasting blood glucose (P < 0.001) and HbA1c levels (P < 0.001). Renal functional and histopathological changes in diabetic and nondiabetic PPARalpha-knockout and wild-type mice were evaluated after 16 weeks of hyperglycemia. PPARalpha immunostaining of the cortical tubules of diabetic wild-type mice was elevated by hyperglycemia. In diabetic PPARalpha-knockout mice, renal disease with accompanying albuminuria, glomerular sclerosis, and mesangial area expansion was more severe than in diabetic wild-type mice (P < 0.05) and was accompanied by increased levels of serum free fatty acids and triglycerides (P < 0.01). Furthermore, they exhibited increased renal immunostaining for type IV collagen and osteopontin, which was associated with increased macrophage infiltration and glomerular apoptosis. There were no significant differences in these indexes of renal disease between nondiabetic PPARalpha-knockout and wild-type mice and diabetic PPARalpha wild-type mice. In vitro studies demonstrated that high glucose levels markedly increased the expression of type IV collagen, transforming growth factor-beta1, and the number of leukocytes adherent to cultured mesangial cells. Adherence of leukocytes was inhibited by the PPARalpha agonist fenofibrate. Taken together, PPARalpha deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating free fatty acid and triglyceride concentrations. PPARalpha agonists may serve as useful therapeutic agents for type 1 diabetic nephropathy.
Park
Cheol Whee
CW
Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, 62, Yoido-Dong, Youngdeungpo-Ku, Seoul, Korea 150-713.
Kim
Hyeong Wook
HW
Ko
Seung Hyun
SH
Chung
Hyun Wha
HW
Lim
Sun Woo
SW
Yang
Chul Woo
CW
Chang
Yoon Sik
YS
Sugawara
Akira
A
Guan
YouFei
Y
Breyer
Matthew D
MD
D000818:Animals; D001794:Blood Pressure; D003094:Collagen / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D011345:Fenofibrate / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053495:Osteopontin; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics*; D012795:Sialoglycoproteins / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
D005230:Fatty Acids, Nonesterified; D008055:Lipids; D047493:PPAR alpha; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D014280:Triglycerides; D053495:Osteopontin; D003094:Collagen; D011345:Fenofibrate