PMID- 29273684
OWN - NLM
STAT- MEDLINE
DCOM- 20190913
LR  - 20190913
IS  - 1479-6813 (Electronic)
IS  - 0952-5041 (Linking)
VI  - 60
IP  - 2
DP  - 2018 Feb
TI  - SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of 
      diabetic nephropathy.
PG  - 145-157
LID - 10.1530/JME-17-0260 [doi]
AB  - c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic 
      nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. 
      However, the mechanism remained unclear. We previously reported that SP600125 
      activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the 
      cellular antioxidant defense system, in the aortas of the diabetic mice. Given 
      the critical role of NRF2 in preventing DN, the present study aimed to test 
      whether or not NRF2 is required for SP600125's protection against DN. To test the 
      role of NRF2 in SP600125's effect, streptozotocin-induced C57BL/6 wild-type (WT) 
      and Nrf2-knockout (KO) diabetic mice were treated in the presence or absence of 
      SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates 
      NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the 
      presence or absence of either SP600125 or JNK siRNA. SP600125 significantly 
      attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, 
      pathological change and dysfunction in the WT, but not the Nrf2 KO mice. SP600125 
      inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, 
      preserved NRF2 protein and facilitated its nuclear translocation in the kidneys 
      of the WT mice, the effects of which were similarly produced by either SP600125 
      or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated 
      HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic 
      genes. The present study demonstrates that NRF2 is required for SP600125's 
      protection against DN. SP600125 activates NRF2 possibly via inhibition of 
      JNK-induced Keap1 expression.
CI  - (c) 2018 Society for Endocrinology.
FAU - Zhang, Huan
AU  - Zhang H
AD  - Operating TheaterChina-Japan Union Hospital of Jilin University, Changchun, 
      Jilin, People's Republic of China.
FAU - Liu, Xiuxia
AU  - Liu X
AD  - Department of Clinical LaboratoryThe Second Hospital of Jilin University, 
      Changchun, Jilin, People's Republic of China.
FAU - Zhou, Shanshan
AU  - Zhou S
AD  - Cardiovascular CenterThe First Hospital of Jilin University, Changchun, Jilin, 
      People's Republic of China.
FAU - Jia, Ye
AU  - Jia Y
AD  - Department of NephrologyThe First Hospital of Jilin University, Changchun, Jilin, 
      People's Republic of China.
FAU - Li, Ying
AU  - Li Y
AD  - Department of DermatologyAffiliated Hospital of Beihua University, Jilin, Jilin, 
      People's Republic of China.
FAU - Song, Yuguo
AU  - Song Y
AD  - Research Institute of Clinical ImmunologyAffiliated Hospital of Beihua 
      University, Jilin, Jilin, People's Republic of China.
AD  - Research Center for Life SciencesBeihua University, Jilin, Jilin, People's 
      Republic of China.
FAU - Wang, Junnan
AU  - Wang J
AD  - Department of CardiologyThe Second Hospital of Jilin University, Changchun, 
      Jilin, People's Republic of China wuhaobaha@jlu.edu.cn jdeywjn@163.com.
FAU - Wu, Hao
AU  - Wu H
AD  - Department of NephrologyThe Second Hospital of Jilin University, Changchun, 
      Jilin, People's Republic of China wuhaobaha@jlu.edu.cn jdeywjn@163.com.
AD  - The '973' National Basic Research Program of ChinaChangchun University of Chinese 
      Medicine, Changchun, Jilin, People's Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171222
PL  - England
TA  - J Mol Endocrinol
JT  - Journal of molecular endocrinology
JID - 8902617
RN  - 0 (Anthracenes)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (RNA, Small Interfering)
RN  - 1TW30Y2766 (pyrazolanthrone)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Albuminuria/etiology
MH  - Animals
MH  - Anthracenes/*pharmacology/*therapeutic use
MH  - Cell Nucleus/drug effects/metabolism
MH  - Diabetic Nephropathies/*drug therapy/genetics/pathology/*prevention & control
MH  - Fibrosis
MH  - Gene Deletion
MH  - Glucose/toxicity
MH  - Inflammation/pathology
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Kelch-Like ECH-Associated Protein 1/genetics/*metabolism
MH  - Kidney/pathology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Oxidative Stress/drug effects
MH  - Protein Transport/drug effects
MH  - RNA, Small Interfering/metabolism
OTO - NOTNLM
OT  - JNK
OT  - KEAP1
OT  - NRF2
OT  - antioxidant
OT  - diabetic nephropathy
EDAT- 2017/12/24 06:00
MHDA- 2019/09/14 06:00
CRDT- 2017/12/24 06:00
PHST- 2017/12/11 00:00 [received]
PHST- 2017/12/22 00:00 [accepted]
PHST- 2017/12/24 06:00 [pubmed]
PHST- 2019/09/14 06:00 [medline]
PHST- 2017/12/24 06:00 [entrez]
AID - JME-17-0260 [pii]
AID - 10.1530/JME-17-0260 [doi]
PST - ppublish
SO  - J Mol Endocrinol. 2018 Feb;60(2):145-157. doi: 10.1530/JME-17-0260. Epub 2017 Dec 
      22.