Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis

被引:122
作者
Kim, Hyosang [1 ]
Moon, Soo Young [1 ]
Kim, Joon-Seok [1 ]
Baek, Chung Hee [1 ]
Kim, Miyeon [1 ]
Min, Ji Yeon [1 ]
Lee, Sang Koo [1 ]
机构
[1] Univ Ulsan, Asan Inst Life Sci, Asan Med Ctr, Dept Internal Med, Seoul, South Korea
关键词
AMP-activated protein kinase; endoplasmic reticulum stress; fibrosis; heme oxygenase-1; metformin; ENDOPLASMIC-RETICULUM STRESS; HEME OXYGENASE-1; URETERAL OBSTRUCTION; METABOLIC SYNDROME; LIVER FIBROSIS; EXPRESSION; KIDNEY; INJURY; MICE; DISEASE;
D O I
10.1152/ajprenal.00495.2014
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si) RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP) 78 and phosphorylated eukaryotic initiation factor-2 alpha through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1 beta riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-beta, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.
引用
收藏
页码:F226 / F236
页数:11
相关论文
共 50 条
[1]   Metformin attenuates streptozotocin-induced diabetic nephropathy in rats through modulation of oxidative stress genes expression [J].
Alhaider, Abdulqader A. ;
Korashy, Hesham M. ;
Sayed-Ahmed, Mohamed M. ;
Mobark, Mohammed ;
Kfoury, Hala ;
Mansour, Mahmoud A. .
CHEMICO-BIOLOGICAL INTERACTIONS, 2011, 192 (03) :233-242
[2]   Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol [J].
Ayala, Pedro ;
Montenegro, Jose ;
Vivar, Raul ;
Letelier, Alan ;
Aranguiz Urroz, Pablo ;
Copaja, Miguel ;
Pivet, Deisy ;
Humeres, Claudio ;
Troncoso, Rodrigo ;
Miguel Vicencio, Jose ;
Lavandero, Sergio ;
Diaz-Araya, Guillermo .
EXPERIMENTAL AND MOLECULAR PATHOLOGY, 2012, 92 (01) :97-104
[3]   Adipocyte Heme Oxygenase-1 Induction Attenuates Metabolic Syndrome in Both Male and Female Obese Mice [J].
Burgess, Angela ;
Li, Ming ;
Vanella, Luca ;
Kim, Dong Hyun ;
Rezzani, Rita ;
Rodella, Luigi ;
Sodhi, Komal ;
Canestraro, Martina ;
Martasek, Pavel ;
Peterson, Stephen J. ;
Kappas, Attallah ;
Abraham, Nader G. .
HYPERTENSION, 2010, 56 (06) :1124-U246
[4]   Endoplasmic Reticulum Stress Implicated in the Development of Renal Fibrosis [J].
Chiang, Chih-Kang ;
Hsu, Shih-Ping ;
Wu, Cheng-Tien ;
Huang, Jenq-Wen ;
Cheng, Hui-Teng ;
Chang, Yi-Wen ;
Hung, Kuan-Yu ;
Wu, Kuan-Dun ;
Liu, Shing-Hwa .
MOLECULAR MEDICINE, 2011, 17 (11-12) :1295-1305
[5]   Carbon monoxide, a reaction product of heme oxygenase-1, suppresses the expression of C-reactive protein by endoplasmic reticulum stress through modulation of the unfolded protein response [J].
Chung, Jihwa ;
Shin, Da-Yong ;
Zheng, Min ;
Joe, Yeonsoo ;
Pae, Hyun-Ock ;
Ryter, Stefan W. ;
Chung, Hun-Taeg .
MOLECULAR IMMUNOLOGY, 2011, 48 (15-16) :1793-1799
[6]   Heme oxygenase 1: Does it have a role in renal cytoprotection? [J].
Courtney, Aisling E. ;
Maxwell, A. Peter .
AMERICAN JOURNAL OF KIDNEY DISEASES, 2008, 51 (04) :678-690
[7]   Endoplasmic reticulum stress in proteinuric kidney disease [J].
Cybulsky, Andrey V. .
KIDNEY INTERNATIONAL, 2010, 77 (03) :187-193
[8]   Heme Oxygenase-1 Inducer Hemin Attenuates the Progression of Remnant Kidney Model [J].
Desbuards, Nicolas ;
Hyvelin, Jean-Marc ;
Machet, Marie-Christine ;
Eder, Veronique ;
Garrigue, Marie-Ange ;
Halimi, Jean-Michel ;
Antier, Daniel .
NEPHRON EXPERIMENTAL NEPHROLOGY, 2009, 113 (01) :E35-E44
[9]   Activation of AMP-Activated Protein Kinase Inhibits Oxidized LDL-Triggered Endoplasmic Reticulum Stress In Vivo (Publication with Expression of Concern. See vol. 72, pg. 1036, 2023) [J].
Dong, Yunzhou ;
Zhang, Miao ;
Wang, Shuangxi ;
Liang, Bin ;
Zhao, Zhengxing ;
Liu, Chao ;
Wu, Mingyuan ;
Choi, Hyoung Chul ;
Lyons, Timothy J. ;
Zou, Ming-Hui .
DIABETES, 2010, 59 (06) :1386-1396
[10]   Involvement of Endoplasmic Reticulum Stress in Albuminuria Induced Inflammasome Activation in Renal Proximal Tubular Cells [J].
Fang, Li ;
Xie, Da ;
Wu, Xian ;
Cao, Hongdi ;
Su, Weifang ;
Yang, Junwei .
PLOS ONE, 2013, 8 (08)