Accelerated Diabetic Nephropathy in Mice Lacking the Peroxisome
Proliferator-Activated Receptor-alpha
Authors Cheol Whee Park, M.D., Hyeong Wook Kim, M.D., Seung Hyun Ko, M.D., Hyun Wha
Chung, M.D., Sun Woo Lim, Ph.D., Chul Woo Yang, M.D., Yoon Sik Chang, M.D.,
Akira Sugawara, M.D., YouFei Guan, M.D., Matthew D. Breyer
Submitted By Matthew Breyer on 1/4/2006
Status Published
Journal Diabetes
Year 2006
Date Published 4/1/2006
Volume : Pages 55 : 885 - 893
PubMed Reference 16567507
Abstract Peroxisome proliferator-activated receptor- (PPAR) is a member of the
ligand-activated nuclear receptor superfamily playing 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 PPAR in the pathogenesis
of diabetic nephropathy using PPAR-knockout (PPAR-KO) mice and cultured mouse
mesangial cells (MCs). Diabetes was induced using a low-dose streptozotocin
protocol in 8-wk-old male 129 SvJ PPAR-KO and WT mice. Diabetic PPAR-KO and WT
mice developed increased fasting blood glucose (p<0.001) and HbA1C levels
(p<0.001). Renal functional and histopathological changes in diabetic and
non-diabetic PPAR- KO and WT were evaluated following 16 weeks of
hyperglycemia. PPAR immunostaining appeared increased cortical tubules of
diabetic WT mice in diabetic WT mice. In diabetic PPAR-KO, renal disease with
accompanying albuminuria, glomerular sclerosis and mesangial area expansion was
more sever than in diabetic WT mice (p<0.05) and was accompanied by increased
serum free fatty acid and triglyceride (p<0.01). Furthermore, there was
increased renal immunostaining for type IV collagen and osteopontin associated
with more macrophage infiltration and glomerular apoptosis. In non-diabetic
PPAR-KO and WT as well as diabetic PPAR WT mice, there were no significant
differences in these indices of renal disease. In vitro studies demonstrated
that high glucose markedly increased the expression of type IV collagen and
number of adherent leukocytes to cultured MCs. The latter finding was inhibited
by the PPAR agonist fenofibrate. Taken together, PPAR deficiency appears to
aggravate the severity of diabetic nephropathy through increase in extracellular
matrix formation and inflammation. PPAR agonists may serve as a useful
therapeutic agent for type I diabetic nephropathy.


Hba-a1hemoglobin alpha, adult chain 1
Pparaperoxisome proliferator activated receptor alpha
Spp1secreted phosphoprotein 1
Tgfbr1transforming growth factor, beta receptor I