PMID- 32777444
OWN - NLM
STAT- MEDLINE
DCOM- 20201102
LR  - 20231213
IS  - 1532-8600 (Electronic)
IS  - 0026-0495 (Linking)
VI  - 111
DP  - 2020 Oct
TI  - Empagliflozin improves diabetic renal tubular injury by alleviating mitochondrial 
      fission via AMPK/SP1/PGAM5 pathway.
PG  - 154334
LID - S0026-0495(20)30198-0 [pii]
LID - 10.1016/j.metabol.2020.154334 [doi]
AB  - BACKGROUND AND PURPOSE: Excessive mitochondrial fission was observed in diabetic 
      kidney disease (DKD). Phosphoglycerate mutase family member 5 (PGAM5) plays an 
      important role in mitochondrial fission by dephosphorylating the dynamin-related 
      protein 1 at Ser637 (DRP1S637). Whether PGAM5 participates in the mitochondrial 
      fission in diabetic renal tubular injury is unknown. Clinical trials have 
      observed encouraging effect of Sodium-glucose cotransporter 2 (SGLT2) inhibitors 
      on DKD though the underling mechanisms remain unclear. EXPERIMENTAL APPROACH: We 
      used KK-Ay mice as diabetic model and Empagliflozin (Empa) were administrated by 
      oral gavage. The mitochondrial fission and the expressions of phosphorylated 
      AMP-activated protein kinase (p-AMPK), specificityprotein1 (SP1), PGAM5 and 
      DRP1S637 were tested. We also examined these changes in HK2 cells that cultured 
      in normal glucose (NG), high glucose (HG) and high glucose+Empa (HG + Empa) 
      environment. Then we verified our deduction using AMPK activator 
      (5-aminoimidazole-4-carboximide Riboside, AICAR), inhibitor (Compound C), si-SP1 
      and si-PGAM5. Lastly, we testified the interaction between SP1 and the 
      PGAM5promotor by CHIP assay. KEY RESULTS: The mitochondrial fission and the 
      expression of SP1, PGAM5 increased and the expression of p-AMPK, DRP1S637 
      decreased in diabetic or HG environment. These changes were all reversed in Empa 
      or AICAR treated groups. These reversal effects of Empa could be diminished by 
      Compound C. Either si-SP1 or si-PGAM5 could alleviate the mitochondrial fission 
      without affection on AMPK phosphorylation. Finally, the CHIP assay confirmed the 
      interaction between SP1 and the PGAM5 promotor. CONCLUSIONS AND IMPLICATIONS: The 
      PGAM5 aggravated the development of diabetic renal tubular injury and the Empa 
      could improve the DKD by alleviating mitochondrial fission via AMPK/SP1/PGAM5 
      pathway.
CI  - Copyright (c) 2020. Published by Elsevier Inc.
FAU - Liu, Xiangyang
AU  - Liu X
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Xu, Chaofei
AU  - Xu C
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Xu, Linxin
AU  - Xu L
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Li, Xiaoyu
AU  - Li X
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Sun, Hongxi
AU  - Sun H
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Xue, Mei
AU  - Xue M
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Li, Ting
AU  - Li T
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Yu, Xiaochen
AU  - Yu X
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China.
FAU - Sun, Bei
AU  - Sun B
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China. Electronic address: 
      sun_peipei220@hotmail.com.
FAU - Chen, Liming
AU  - Chen L
AD  - NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of 
      Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital 
      &Tianjin Institute of Endocrinology, Tianjin 300070, China. Electronic address: 
      xfx22081@vip.163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200807
PL  - United States
TA  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Glucosides)
RN  - 0 (SLC5A2 protein, human)
RN  - 0 (Sodium-Glucose Transporter 2)
RN  - 0 (Sp1 Transcription Factor)
RN  - 0 (SP1 protein, human)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - HDC1R2M35U (empagliflozin)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Benzhydryl Compounds/*pharmacology
MH  - Cell Line
MH  - Diabetic Nephropathies/*drug therapy/metabolism
MH  - Glucosides/*pharmacology
MH  - Humans
MH  - Kidney Tubules/*drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondrial Dynamics/*drug effects
MH  - Phosphorylation/drug effects
MH  - Signal Transduction/drug effects
MH  - Sodium-Glucose Transporter 2/*metabolism
MH  - Sp1 Transcription Factor/*metabolism
OTO - NOTNLM
OT  - AMP-activated protein kinases
OT  - Diabetic nephropathies
OT  - Mitochondrial dynamics
OT  - Sodium-glucose transporter 2 inhibitors
COIS- Declaration of competing interest The authors have declared that no competing 
      interest exists.
EDAT- 2020/08/11 06:00
MHDA- 2020/11/03 06:00
CRDT- 2020/08/11 06:00
PHST- 2020/04/19 00:00 [received]
PHST- 2020/08/01 00:00 [revised]
PHST- 2020/08/04 00:00 [accepted]
PHST- 2020/08/11 06:00 [pubmed]
PHST- 2020/11/03 06:00 [medline]
PHST- 2020/08/11 06:00 [entrez]
AID - S0026-0495(20)30198-0 [pii]
AID - 10.1016/j.metabol.2020.154334 [doi]
PST - ppublish
SO  - Metabolism. 2020 Oct;111:154334. doi: 10.1016/j.metabol.2020.154334. Epub 2020 
      Aug 7.