Author
Listed:
- Yu Ah Hong
- Ji Hee Lim
- Min Young Kim
- Tae Woo Kim
- Yaeni Kim
- Keun Suk Yang
- Hoon Suk Park
- Sun Ryoung Choi
- Sungjin Chung
- Hyung Wook Kim
- Hye Won Kim
- Bum Soon Choi
- Yoon Sik Chang
- Cheol Whee Park
Abstract
Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.
Suggested Citation
Yu Ah Hong & Ji Hee Lim & Min Young Kim & Tae Woo Kim & Yaeni Kim & Keun Suk Yang & Hoon Suk Park & Sun Ryoung Choi & Sungjin Chung & Hyung Wook Kim & Hye Won Kim & Bum Soon Choi & Yoon Sik Chang & Ch, 2014.
"Fenofibrate Improves Renal Lipotoxicity through Activation of AMPK-PGC-1α in db/db Mice,"
PLOS ONE, Public Library of Science, vol. 9(5), pages 1-14, May.
Handle:
RePEc:plo:pone00:0096147
DOI: 10.1371/journal.pone.0096147
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