Peroxisome proliferator-activated receptor-δ activation ameliorates albuminuria by preventing nephrin loss and restoring podocyte integrity in type 2 diabetes.
BACKGROUND
Peroxisome proliferator-activated receptor (PPAR)-δ is a ligand-activated transcription factor in regulating gene expression and is believed to play an important role in various kidney diseases including diabetic nephropathy. This study investigated the efficacy of GW610742, a highly specific agonist for PPAR-δ, for the treatment of diabetic nephropathy.


METHODS
Type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats were randomized into an untreated diabetic group (n = 9) and a GW610742-treated diabetic group (n= 9). The GW610742 was administered (10 mg/kg/day) orally for 11 weeks. Long-Evans Tokushima Otsuka rats (n = 9) were used as a non-diabetic control.


RESULTS
Albuminuria was markedly increased and renal PPAR-δ expression was decreased in diabetes. Diabetic albuminuria and renal injury markers, such as glomerular basement membrane thickening, decreased number of slit pores between podocyte foot processes, decreased nephrin expression, increased desmin expression and increased CCL2 expression, were significantly reversed through the treatment with GW610742. PPAR-δ agonist GW610742 markedly increased nephrin expression in cultured podocytes. Nephrin mRNA expression was markedly decreased in response to high glucose in cultured podocytes and effectively prevented by GW610742.


CONCLUSIONS
PPAR-δ activation by GW610742 ameliorates albuminuria by preventing diabetes-induced nephrin loss and restoring podocyte integrity, implying that GW610742 may be a potential therapeutic agent for diabetic nephropathy.
Department of Internal Medicine, Soon Chun Hyang University Cheonan Hospital, Cheonan, Korea.
Eun Young
EY
Lee
Geun Tae
GT
Kim
Miri
M
Hyun
Suji
S
Kim
Sujin
S
Seok
Ran
R
Choi
Mi Young
MY
Lee
Choon Hee
CH
Chung
D000419:Albuminuria / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D060888:Real-Time Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*
C503394:GW 610742; D008565:Membrane Proteins; D047495:PPAR gamma; D013844:Thiazoles; C113267:nephrin