PMID- 31825802
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20210618
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 152
DP  - 2020 May 20
TI  - Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in 
      unilateral ureteral obstruction.
PG  - 632-649
LID - S0891-5849(19)31684-3 [pii]
LID - 10.1016/j.freeradbiomed.2019.12.005 [doi]
AB  - Mitophagy is a principle mechanism to degrade damaged mitochondria through 
      PARK2-dependent or PARK2-independent pathway. Mitophagy has been identified to 
      play an important role in acute kidney disease, whereas its role in renal 
      fibrosis remains ill-defined. We sought to investigate the involvement and 
      regulation of mitophagy in renal tubular epithelial cell(RTEC) injury and renal 
      fibrosis after unilateral ureteral obstruction(UUO). Mitochondrial damageand 
      mitochondrial reactive oxygen species (ROS) production was increased in kidney 
      after obstruction of the left ureter. Mitophagy was increased in kidneys 
      following UUO and HK-2 cells under hypoxia exposure, assessed by electron 
      microscopy of mitophagosome, colocalization of MitotrackerRed-stained 
      mitochondria and LC3 staining. The upregulation of PINK1, PARK2, and LC3 II in 
      mitochondrial fraction was observed in the obstructed kidney and hypoxia-exposed 
      HK-2 cells. Pink1 or Park2 gene deletion markedly increased mtROS production, 
      mitochondrial damage, TGFbeta1 expression in RTEC, and renal fibrosis in UUO. 
      Mitochondrial recruitment of Drp1 was also induced after UUO. The Drp1 inhibitor, 
      Mdivi-1, decreased mitochondrial PINK1, PARK2 and LC3II level, increased mtROS 
      production both in vivo and in vitro, activated TGFbeta1-Smad2/3 signaling in 
      HK-2 cells under hypoxia and worsened renal fibrosis following UUO. The 
      upregulation of TGFbeta1 signaling in hypoxia-treated HK-2 cells due to PINK1 or 
      PARK2 silencing, or worsened renal fibrosis after UUO due to Pink1-or Park2-KO 
      mice was rescued by mitoTEMPO, a mitochondria-targeted antioxidant. The findings 
      of this study suggest that Drp1-regulated PARK2-dependent mitophagy plays a 
      critical role in hypoxia-induced renal tubular epithelial cell injury and renal 
      fibrosis in UUO.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Li, Shu
AU  - Li S
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Lin, Qisheng
AU  - Lin Q
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Shao, Xinghua
AU  - Shao X
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Zhu, Xuying
AU  - Zhu X
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Wu, Jingkui
AU  - Wu J
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Wu, Bei
AU  - Wu B
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Zhang, Minfang
AU  - Zhang M
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Zhou, Wenyan
AU  - Zhou W
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Zhou, Yijun
AU  - Zhou Y
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Jin, Haijiao
AU  - Jin H
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Zhang, Zhen
AU  - Zhang Z
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Qi, Chaojun
AU  - Qi C
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Shen, Jianxiao
AU  - Shen J
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Mou, Shan
AU  - Mou S
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Gu, Leyi
AU  - Gu L
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China.
FAU - Ni, Zhaohui
AU  - Ni Z
AD  - Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, 200127, China. Electronic address: profnizh@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191209
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - EC 2.7.- (Protein Kinases)
SB  - IM
MH  - Animals
MH  - Fibrosis
MH  - *Kidney Diseases/genetics
MH  - Mice
MH  - Mitophagy
MH  - Protein Kinases/genetics
MH  - *Ureteral Obstruction/genetics
OTO - NOTNLM
OT  - Mitochondrial damage
OT  - Mitophagy
OT  - ROS
OT  - Renal fibrosis
OT  - TGFbeta1
COIS- Declaration of competing interest
 The authors declare that they have no 
      conflicts of interest.
EDAT- 2019/12/12 06:00
MHDA- 2021/06/22 06:00
CRDT- 2019/12/12 06:00
PHST- 2019/10/08 00:00 [received]
PHST- 2019/11/22 00:00 [revised]
PHST- 2019/12/05 00:00 [accepted]
PHST- 2019/12/12 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2019/12/12 06:00 [entrez]
AID - S0891-5849(19)31684-3 [pii]
AID - 10.1016/j.freeradbiomed.2019.12.005 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2020 May 20;152:632-649. doi: 
      10.1016/j.freeradbiomed.2019.12.005. Epub 2019 Dec 9.