PMID- 38311057
OWN - NLM
STAT- Publisher
LR  - 20240204
IS  - 2233-6087 (Electronic)
IS  - 2233-6079 (Linking)
DP  - 2024 Feb 1
TI  - Reducing Oxidative Stress and Inflammation by Pyruvate Dehydrogenase Kinase 4 
      Inhibition Is Important in Prevention of Renal Ischemia-Reperfusion Injury in 
      Diabetic Mice.
LID - 10.4093/dmj.2023.0196 [doi]
AB  - BACKGROUND: Reactive oxygen species (ROS) and inflammation are reported to have a 
      fundamental role in the pathogenesis of ischemia-reperfusion (IR) injury, a 
      leading cause of acute kidney injury. The present study investigated the role of 
      pyruvate dehydrogenase kinase 4 (PDK4) in ROS production and inflammation 
      following IR injury. METHODS: We used a streptozotocin-induced diabetic C57BL6/J 
      mouse model, which was subjected to IR by clamping both renal pedicles. Cellular 
      apoptosis and inflammatory markers were evaluated in NRK-52E cells and mouse 
      primary tubular cells after hypoxia and reoxygenation using a hypoxia work 
      station. RESULTS: Following IR injury in diabetic mice, the expression of PDK4, 
      rather than the other PDK isoforms, was induced with a marked increase in 
      pyruvate dehydrogenase E1alpha (PDHE1alpha) phosphorylation. This was accompanied by a 
      pronounced ROS activation, as well as tumor necrosis factor-alpha (TNF-alpha), 
      interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and monocyte chemoattractant 
      protein-1 (MCP-1) production. Notably, sodium dichloroacetate (DCA) attenuated 
      renal IR injury-induced apoptosis which can be attributed to reducing PDK4 
      expression and PDHE1alpha phosphorylation levels. DCA or shPdk4 treatment reduced 
      oxidative stress and decreased TNF-alpha, IL-6, IL-1beta, and MCP-1 production after IR 
      or hypoxia-reoxygenation injury. CONCLUSION: PDK4 inhibition alleviated renal 
      injury with decreased ROS production and inflammation, supporting a critical role 
      for PDK4 in IR mediated damage. This result indicates another potential target 
      for reno-protection during IR injury; accordingly, the role of PDK4 inhibition 
      needs to be comprehensively elucidated in terms of mitochondrial function during 
      renal IR injury.
FAU - Khang, Ah Reum
AU  - Khang AR
AD  - Department of Internal Medicine, Pusan National University Yangsan Hospital, 
      Pusan National University School of Medicine, Yangsan, Korea.
FAU - Kim, Dong Hun
AU  - Kim DH
AD  - Department of Biomedical Science, Graduate School, Kyungpook National University, 
      Daegu, Korea.
FAU - Kim, Min-Ji
AU  - Kim MJ
AD  - Department of Internal Medicine, Kyungpook National University Chilgok Hospital, 
      School of Medicine, Kyungpook National University, Daegu, Korea.
FAU - Oh, Chang Joo
AU  - Oh CJ
AD  - Research Institute of Aging and Metabolism, School of Medicine, Kyungpook 
      National University, Daegu, Korea.
FAU - Jeon, Jae-Han
AU  - Jeon JH
AD  - Department of Internal Medicine, Kyungpook National University Chilgok Hospital, 
      School of Medicine, Kyungpook National University, Daegu, Korea.
AD  - Leading-edge Research Center for Drug Discovery and Development for Diabetes and 
      Metabolic Disease, Kyungpook National University Hospital, Daegu, Korea.
FAU - Choi, Sung Hee
AU  - Choi SH
AD  - Department of Internal Medicine, Seoul National University Bundang Hospital, 
      Seoul National University College of Medicine, Seongnam, Korea.
FAU - Lee, In-Kyu
AU  - Lee IK
AD  - Research Institute of Aging and Metabolism, School of Medicine, Kyungpook 
      National University, Daegu, Korea.
AD  - Leading-edge Research Center for Drug Discovery and Development for Diabetes and 
      Metabolic Disease, Kyungpook National University Hospital, Daegu, Korea.
AD  - Department of Internal Medicine, Kyungpook National University Hospital, School 
      of Medicine, Kyungpook National University, Daegu, Korea.
LA  - eng
PT  - Journal Article
DEP - 20240201
PL  - Korea (South)
TA  - Diabetes Metab J
JT  - Diabetes & metabolism journal
JID - 101556588
SB  - IM
OTO - NOTNLM
OT  - Acute kidney injury
OT  - Diabetes mellitus
OT  - Inflammation
OT  - Ischemia
OT  - Pyruvate dehydrogenase kinase 4
OT  - Reactive oxygen species
OT  - Reperfusion
EDAT- 2024/02/05 00:42
MHDA- 2024/02/05 00:42
CRDT- 2024/02/04 19:28
PHST- 2023/06/22 00:00 [received]
PHST- 2023/07/13 00:00 [accepted]
PHST- 2024/02/05 00:42 [medline]
PHST- 2024/02/05 00:42 [pubmed]
PHST- 2024/02/04 19:28 [entrez]
AID - dmj.2023.0196 [pii]
AID - 10.4093/dmj.2023.0196 [doi]
PST - aheadofprint
SO  - Diabetes Metab J. 2024 Feb 1. doi: 10.4093/dmj.2023.0196.