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논문분류	춘계학술대회 초록집
제목	Fenofibrate Ameliorates Diabetic Nephropathy Though the Activation of AMPK-PGC-1α-ERR-1α Signaling in db/db Mice
저자	Yu Ah Hong1, Min Young Kim2, Ji Hee Lim2, Keun-Suk Yang2, Sun Ryoung Choi2, Sungjin Chung2, Seok Joon Shin2, Bum Soon Choi2, Hyung Wook Kim2, Yong Soo Kim2, Yoon Sik Chang2, Cheol Whee Park2
출판정보	2013; 2013(1):
키워드	당뇨병성 신증, fenofibrate, PGC-1α/ Daibetic nephropathy, Fenofibrate, PGC-1α
초록	The peroxisome proliferative-activate receptor-α (PPARα) is a lipid-sensing transcriptional factor that has a role in gluco-oxidative stress and lipotoxicity. AMP-kinase (AMPK) and peroxisome proliferative-activated receptor gamma coactivator (PGC)-1α is a multifunctional transcriptional protein, acts as a ‘molecular switch’ in pathways controlling fatty acid oxidation and oxidative stress, and may be a critical link in the pathogenesis of type 2 diabetes and metabolic syndrome associated with estrogen-related receptor (ERR)-1α. We evaluated the renoprotective effect of fenofibrate agonist lipotoxicity through the change of AMPK-PGC-1α-ERRα and their downstream PI3K-Akt-FoxOs on diabetic nephropathy in db/db mice. Male C57 BLKS db/db mice and db/m controls at 8 weeks of age were divided to receive either a regular diet chow or a diet containing fenofibrate (0.2% wt/wt, n=6, respectively). Mice were followed for 12 weeks and were evaluated about renal functional and pathologic phenotypes and the PPARα-AMPK-PGC-1α-ERR-1α pathway. Fenofibrate treatment slightly reduced fasting blood glucose (p<0.05) and HbA1c levels (p<0.05) in db/db mice. Fenofibrate also ameliorated albuminuria (P<0.001) and decreased urine volume (p<0.001) in db/db mice. The mesangial area expansion, inflammatory cell infiltration, and the accumulation of intra-renal free fatty acid and triglycerides were observed in db/db mice. A downregulation of PPARα suppressed AMPK-PGC-1α and ERR-1α expressions and increased PI3K-Akt-phosphorylation of FoxO3a, not FoxO1, in the kidney, which led to oxidative stress and decreases fatty acid oxidation. Treatment of fenofibrate increased the PPARα expression and subsequently activated the AMPK-PGC-1α-ERR-1α and suppressed PI3K-Akt-phosphorylation of FoxO3a signaling. In cultured mesangial cells, suppressed AMPK-PGC-1α-ERR-1α and increased PI3K-Akt-phosphorylation of FoxO3a signaling in high-glucose media reversed by fenofibrate, which was associated with decreases in oxidative stress and apoptosis. In conclusion, the results suggest that PPARα agonist fenofibrate improves lipotoxicity through activation of the AMPK-PGC-1α-ERR-1α signaling and may be a potentially therapeutic modality for type 2 diabetic nephropathy.
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