Metformin attenuates renal fibrosis in both AMPKα2-dependent and independent manners

被引:43
作者
Feng, Yenan [1 ,2 ,3 ,4 ]
Wang, Shuaixing [1 ,2 ,3 ,4 ]
Zhang, Youyi [1 ,2 ,3 ,4 ]
Xiao, Han [1 ,2 ,3 ,4 ]
机构
[1] Peking Univ, Hosp 3, Inst Vasc Med, Beijing, Peoples R China
[2] Minist Hlth, Key Lab Cardiovasc Mol Biol & Regulatory Peptides, Beijing, Peoples R China
[3] Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
[4] Beijing Key Lab Cardiovasc Receptors Res, Beijing, Peoples R China
来源
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY | 2017年 / 44卷 / 06期
基金
中国国家自然科学基金;
关键词
AMPK alpha 2; metformin; renal fibrosis; TGF beta 1; ACTIVATED PROTEIN-KINASE; TGF-BETA; INTERSTITIAL FIBROSIS; EXPRESSION; PATHWAY; ALPHA-2; STRESS; DISEASES; INJURY; CELLS;
D O I
10.1111/1440-1681.12748
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Metformin is a well-known AMP-activated protein kinase (AMPK) activator, and it has been shown to inhibit organ fibrosis. Whether AMPK alpha 2 mediates metformin protection against renal fibrosis remains unknown. Here, we aimed to investigate the role of the AMPK alpha 2 isoform in mediating the inhibitory effect of metformin on renal fibrosis. Unilateral ureteral obstruction (UUO) was used to induce renal fibrosis in wild-type (WT) and AMPK alpha 2 knockout (AMPK alpha 2(-/-)) mice. Metformin treatment was initiated 3 days before UUO and was continued until 7 days after UUO. In WT mice, metformin significantly inhibited UUO-induced renal fibrosis. In AMPK alpha 2(-/-) mice, metformin also tended to inhibit UUO-induced renal fibrosis. Specifically, metformin significantly -reduced UUO-induced transforming growth factor beta 1 (TGF beta 1) mRNA and protein -expression in WT mice but not in AMPK alpha 2(-/-) mice. In contrast, metformin reduced UUO-induced TGF beta 1 downstream Smad3 phosphorylation in both WT and AMPK alpha 2(-/-) mice, suggesting that this regulation occurs in an AMPK alpha 2-independent manner. In conclusion, the underlying mechanisms for the protective effects of metformin against renal fibrosis include AMPK alpha 2-dependent targeting of TGF beta 1 production and AMPK alpha 2-independent targeting of TGF beta 1 downstream signalling. In this regard, metformin has an advantage over other AMPK activators for the treatment of renal fibrosis.
引用
收藏
页码:648 / 655
页数:8
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