PMID- 25428127
OWN - NLM
STAT- MEDLINE
DCOM- 20150325
LR  - 20220318
IS  - 1522-1466 (Electronic)
IS  - 1522-1466 (Linking)
VI  - 308
IP  - 3
DP  - 2015 Feb 1
TI  - Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis.
PG  - F226-36
LID - 10.1152/ajprenal.00495.2014 [doi]
AB  - 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-2alpha 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-1beta 
      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.
CI  - Copyright (c) 2015 the American Physiological Society.
FAU - Kim, Hyosang
AU  - Kim H
AD  - Department of Internal Medicine, Asan Medical Center, Asan Institute for Life 
      Sciences, University of Ulsan, Seoul, Korea.
FAU - Moon, Soo Young
AU  - Moon SY
AD  - Department of Internal Medicine, Asan Medical Center, Asan Institute for Life 
      Sciences, University of Ulsan, Seoul, Korea.
FAU - Kim, Joon-Seok
AU  - Kim JS
AD  - Department of Internal Medicine, Asan Medical Center, Asan Institute for Life 
      Sciences, University of Ulsan, Seoul, Korea.
FAU - Baek, Chung Hee
AU  - Baek CH
AD  - Department of Internal Medicine, Asan Medical Center, Asan Institute for Life 
      Sciences, University of Ulsan, Seoul, Korea.
FAU - Kim, Miyeon
AU  - Kim M
AD  - Department of Internal Medicine, Asan Medical Center, Asan Institute for Life 
      Sciences, University of Ulsan, Seoul, Korea.
FAU - Min, Ji Yeon
AU  - Min JY
AD  - Department of Internal Medicine, Asan Medical Center, Asan Institute for Life 
      Sciences, University of Ulsan, Seoul, Korea.
FAU - Lee, Sang Koo
AU  - Lee SK
AD  - Department of Internal Medicine, Asan Medical Center, Asan Institute for Life 
      Sciences, University of Ulsan, Seoul, Korea sklee2@amc.seoul.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141126
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Hspa5 protein, mouse)
RN  - 11089-65-9 (Tunicamycin)
RN  - 9100L32L2N (Metformin)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Disease Models, Animal
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Enzyme Activation
MH  - Fibrosis/metabolism
MH  - Heat-Shock Proteins/metabolism
MH  - Heme Oxygenase-1/*metabolism
MH  - Humans
MH  - Kidney Diseases/*drug therapy
MH  - Male
MH  - Metformin/*pharmacology
MH  - Mice, Inbred C57BL
MH  - Tunicamycin/pharmacology
OTO - NOTNLM
OT  - AMP-activated protein kinase
OT  - endoplasmic reticulum stress
OT  - fibrosis
OT  - heme oxygenase-1
OT  - metformin
EDAT- 2014/11/28 06:00
MHDA- 2015/03/26 06:00
CRDT- 2014/11/28 06:00
PHST- 2014/11/28 06:00 [entrez]
PHST- 2014/11/28 06:00 [pubmed]
PHST- 2015/03/26 06:00 [medline]
AID - ajprenal.00495.2014 [pii]
AID - 10.1152/ajprenal.00495.2014 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2015 Feb 1;308(3):F226-36. doi: 
      10.1152/ajprenal.00495.2014. Epub 2014 Nov 26.