Diabetes & Metabolism Journal

Chang Joo Oh

2 Articles

Basic research
Reducing Oxidative Stress and Inflammation by Pyruvate Dehydrogenase Kinase 4 Inhibition Is Important in Prevention of Renal Ischemia-Reperfusion Injury in Diabetic Mice: Ah Reum Khang, Dong Hun Kim, Min-Ji Kim, Chang Joo Oh, Jae-Han Jeon, Sung Hee Choi, In-Kyu Lee; Diabetes Metab J. 2024;48(3):405-417. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0196

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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 E1α (PDHE1α) phosphorylation. This was accompanied by a pronounced ROS activation, as well as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), 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 PDHE1α phosphorylation levels. DCA or shPdk4 treatment reduced oxidative stress and decreased TNF-α, IL-6, IL-1β, 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.

Citations

Citations to this article as recorded by

Exploring Renal Pyruvate Metabolism as a Therapeutic Avenue for Diabetic Kidney Injury
Jaemin Lee
Diabetes & Metabolism Journal.2024; 48(3): 385. CrossRef
Cardiovascular Disease and miRNAs: Possible Oxidative Stress-Regulating Roles of miRNAs
Seahyoung Lee
Antioxidants.2024; 13(6): 656. CrossRef
Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4
Chang Joo Oh, Wooyoung Choi, Ha Young Lee, In-Kyu Lee, Min-Ji Kim, Jae-Han Jeon
Biomedicines.2024; 12(12): 2815. CrossRef

Basic Research
CycloZ Improves Hyperglycemia and Lipid Metabolism by Modulating Lysine Acetylation in KK-Ay Mice: Jongsu Jeon, Dohyun Lee, Bobae Kim, Bo-Yoon Park, Chang Joo Oh, Min-Ji Kim, Jae-Han Jeon, In-Kyu Lee, Onyu Park, Seoyeong Baek, Chae Won Lim, Dongryeol Ryu, Sungsoon Fang, Johan Auwerx, Kyong-Tai Kim, Hoe-Yune Jung; Diabetes Metab J. 2023;47(5):653-667. Published online April 26, 2023; DOI: https://doi.org/10.4093/dmj.2022.0244

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Abstract PDF Supplementary Material PubReader ePub

Background
CycloZ, a combination of cyclo-His-Pro and zinc, has anti-diabetic activity. However, its exact mode of action remains to be elucidated.
Methods
KK-Ay mice, a type 2 diabetes mellitus (T2DM) model, were administered CycloZ either as a preventive intervention, or as a therapy. Glycemic control was evaluated using the oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels. Liver and visceral adipose tissues (VATs) were used for histological evaluation, gene expression analysis, and protein expression analysis.
Results
CycloZ administration improved glycemic control in KK-Ay mice in both prophylactic and therapeutic studies. Lysine acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, liver kinase B1, and nuclear factor-κB p65 was decreased in the liver and VATs in CycloZ-treated mice. In addition, CycloZ treatment improved mitochondrial function, lipid oxidation, and inflammation in the liver and VATs of mice. CycloZ treatment also increased the level of β-nicotinamide adenine dinucleotide (NAD⁺), which affected the activity of deacetylases, such as sirtuin 1 (Sirt1).
Conclusion
Our findings suggest that the beneficial effects of CycloZ on diabetes and obesity occur through increased NAD⁺ synthesis, which modulates Sirt1 deacetylase activity in the liver and VATs. Given that the mode of action of an NAD+ booster or Sirt1 deacetylase activator is different from that of traditional T2DM drugs, CycloZ would be considered a novel therapeutic option for the treatment of T2DM.

Citations

Citations to this article as recorded by

Cyclo His‐Pro Attenuates Muscle Degeneration in Murine Myopathy Models
Alessia De Masi, Nadège Zanou, Keno Strotjohann, Dohyun Lee, Tanes I. Lima, Xiaoxu Li, Jongsu Jeon, Nicolas Place, Hoe‐Yune Jung, Johan Auwerx
Advanced Science.2024;[Epub] CrossRef
CycloZ Suppresses TLR4-Driven Inflammation to Reduce Asthma-Like Responses in HDM-Exposed Mouse Models
Dohyun Lee, Jongsu Jeon, Seoyeong Baek, Onyu Park, Ah-Ram Kim, Myoung-Sool Do, Hoe-Yune Jung
Cells.2024; 13(23): 2034. CrossRef
Cyclic Peptides as Protein Kinase Modulators and Their Involvement in the Treatment of Diverse Human Diseases
Lorena Martínez-Alcantar, Laura Hernández-Padilla, Alma Laura Díaz-Pérez, Lizbeth Guadalupe Villalón-Magallán, Mayra Xóchitl Durán-Maldonado, César Díaz-Pérez, Marlene E. Campos-Morales, Citlali Figueroa-Guzmán, Jesús Campos-García
Kinases and Phosphatases.2024; 2(4): 346. CrossRef

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