PMID- 31655022
OWN - NLM
STAT- MEDLINE
DCOM- 20210419
LR  - 20210419
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 177
IP  - 2
DP  - 2020 Jan
TI  - FOXO1 inhibition prevents renal ischemia-reperfusion injury via cAMP-response 
      element binding protein/PPAR-gamma coactivator-1alpha-mediated mitochondrial biogenesis.
PG  - 432-448
LID - 10.1111/bph.14878 [doi]
AB  - BACKGROUND AND PURPOSE: Growing evidence indicates targeting mitochondrial 
      dynamics and biogenesis could accelerate recovery from renal ischemia-reperfusion 
      (I/R) injury, but the underlying mechanisms remain elusive. Transcription factor 
      forkhead box O1 (FOXO1) is a key regulator of mitochondrial homeostasis and plays 
      a pathological role in the progression of renal disease. EXPERIMENTAL APPROACH: A 
      mouse model of renal I/R injury and a hypoxia/reoxygenation (H/R) injury model 
      for human renal tubular epithelial cells were used. KEY RESULTS: I/R injury 
      up-regulated renal expression of FOXO1 and treatment with FOXO1-selective 
      inhibitor AS1842856 prior to I/R injury decreased serum urea nitrogen, serum 
      creatinine and the tubular damage score after injury. Post-I/R injury AS1842856 
      treatment could also ameliorate renal function and improve the survival rate of 
      mice following injury. AS1842856 administration reduced mitochondrial-mediated 
      apoptosis, suppressed the overproduction of mitochondrial ROS and accelerated 
      recovery of ATP both in vivo and in vitro. Additionally, FOXO1 inhibition 
      improved mitochondrial biogenesis and suppressed mitophagy. Expression of PPAR-gamma 
      coactivator 1alpha (PGC-1alpha), a master regulator of mitochondrial biogenesis, was 
      down-regulated in both I/R and H/R injury, which could be abrogated by FOXO1 
      inhibition. Experiments using integrated bioinformatics analysis and 
      coimmunoprecipitation established that FOXO1 inhibited PGC-1alpha transcription by 
      competing with cAMP-response element binding protein (CREB) for its binding to 
      transcriptional coactivators CREBBP/EP300 (CBP/P300). CONCLUSION AND 
      IMPLICATIONS: These findings suggested that FOXO1 was critical to maintain 
      mitochondrial function in renal tubular epithelial cells and FOXO1 may serve as a 
      therapeutic target for pharmacological intervention in renal I/R injury.
CI  - (c) 2019 The British Pharmacological Society.
FAU - Wang, Di
AU  - Wang D
AUID- ORCID: 0000-0002-1847-7283
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of 
      Tumor Systems Biology, Peking University, Beijing, China.
FAU - Wang, Yanqing
AU  - Wang Y
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of 
      Tumor Systems Biology, Peking University, Beijing, China.
AD  - Research Center of Integrative Medicine, School of Basic Medical Sciences, 
      Guangzhou University of Chinese Medicine, Guangzhou, China.
FAU - Zou, Xiantong
AU  - Zou X
AD  - Department of Endocrinology and Metabolism, Peking University People's Hospital, 
      Beijing, China.
FAU - Shi, Yundi
AU  - Shi Y
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of 
      Tumor Systems Biology, Peking University, Beijing, China.
FAU - Liu, Qian
AU  - Liu Q
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of 
      Tumor Systems Biology, Peking University, Beijing, China.
FAU - Huyan, Tianru
AU  - Huyan T
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of 
      Tumor Systems Biology, Peking University, Beijing, China.
FAU - Su, Jing
AU  - Su J
AD  - Department of Pathology, School of Basic Medical Sciences, Peking University, 
      Beijing, China.
FAU - Wang, Qi
AU  - Wang Q
AD  - Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, 
      Guangzhou, China.
FAU - Zhang, Fengxue
AU  - Zhang F
AD  - Research Center of Integrative Medicine, School of Basic Medical Sciences, 
      Guangzhou University of Chinese Medicine, Guangzhou, China.
FAU - Li, Xuejun
AU  - Li X
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of 
      Tumor Systems Biology, Peking University, Beijing, China.
FAU - Tie, Lu
AU  - Tie L
AUID- ORCID: 0000-0003-4755-2091
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of 
      Tumor Systems Biology, Peking University, Beijing, China.
LA  - eng
GR  - JRCC2011/Fund of Janssen Research Council China/International
GR  - BMU20110254/Leading Academic Discipline Project of Beijing Education 
      Bureau/International
GR  - ZZ16019/Beijing Golden Bridge Seed Capital Project/International
GR  - YETP0053/Beijing Higher Education Young Elite Teacher Project/International
GR  - 7172119/Beijing Natural Science Foundation/International
GR  - 30901803/National Natural Science Foundation of China/International
GR  - 81373405/National Natural Science Foundation of China/International
GR  - 81473235/National Natural Science Foundation of China/International
GR  - 81673453/National Natural Science Foundation of China/International
GR  - 81673486/National Natural Science Foundation of China/International
GR  - 81874318/National Natural Science Foundation of China/International
GR  - 81974506/National Natural Science Foundation of China/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191223
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 
      (5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic 
      acid)
RN  - 0 (CREB1 protein, human)
RN  - 0 (Creb1 protein, mouse)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Quinolones)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Line
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - Disease Models, Animal
MH  - Forkhead Box Protein O1/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Kidney Diseases/metabolism/pathology/*prevention & control
MH  - Kidney Tubules/*drug effects/metabolism/pathology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mitochondria/*drug effects/metabolism/pathology
MH  - Mitophagy/drug effects
MH  - *Organelle Biogenesis
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism
MH  - Quinolones/*pharmacology
MH  - Reperfusion Injury/metabolism/pathology/*prevention & control
MH  - Signal Transduction
PMC - PMC6989953
COIS- The authors declare no conflicts of interest.
EDAT- 2019/10/28 06:00
MHDA- 2021/04/20 06:00
PMCR- 2021/01/01
CRDT- 2019/10/27 06:00
PHST- 2019/03/16 00:00 [received]
PHST- 2019/08/29 00:00 [revised]
PHST- 2019/09/03 00:00 [accepted]
PHST- 2019/10/28 06:00 [pubmed]
PHST- 2021/04/20 06:00 [medline]
PHST- 2019/10/27 06:00 [entrez]
PHST- 2021/01/01 00:00 [pmc-release]
AID - BPH14878 [pii]
AID - 10.1111/bph.14878 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2020 Jan;177(2):432-448. doi: 10.1111/bph.14878. Epub 2019 Dec 
      23.