Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
PUM2 Lowers HDAC9 mRNA Stability to Improve Contrast-Induced Acute Kidney Injury through Attenuating Oxidative Stress and Promoting Autophagy: Wei Chen, Hengcheng Lu, Wenni Dai, Hao Li, Yinyin Chen, Guoyong Liu, Liyu He; Received July 18, 2024 Accepted May 21, 2025 Published online September 10, 2025; DOI: https://doi.org/10.4093/dmj.2024.0396 [Epub ahead of print]

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Background
Contrast-induced acute kidney injury (CIAKI) is the third cause of hospital-acquired acute kidney injury and diabetes mellitus (DM) was identified as a risk factor for CIAKI. However, the molecular mechanism underlying DM-CIAKI remains unclear, which needs further investigation.
Methods
DM-CIAKI models of mice and cells were established. The functions of kidneys were evaluated by detecting indicators and using hematoxylin and eosin staining. The abundance of genes and proteins was evaluated by real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, immunofluorescence, and Western blot. Glutathione peroxidase, superoxide dismutase, and malondialdehyde were measured using commercial kits and reactive oxygen species was detected using dihydroethidium (DHE) probe and 2ʹ,7ʹ-dichloroflfluorescein diacetate (DCFH-DA) method. Apoptosis of tissues and cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Cell viability and proliferation were measured using Cell Counting Kit-8 and 5-ethynyl-2ʹ-deoxyuridine (EdU) assay. The interaction between pumilio RNA binding family member 2 (PUM2) and histone deacetylase 9 (HDAC9) was validated using RNA immunoprecipitation (RIP) and RNA pull-down.
Results
PUM2 expression was observably reduced in DM-CIAKI models while HDAC9 expression was notably boosted. Subsequently, PUM2 silencing resulted in aggravation of kidney injury in DM-CIAKI mice through enhancing oxidative stress and suppressing autophagy, while HDAC9 inhibitor or HDAC9 silencing achieved the opposite results. In terms of mechanism, PUM2 could suppress stability of HDAC9 mRNA to attenuate HDAC9 expression. Furthermore, HDAC9 overexpression abolished PUM2 overexpression-mediated oxidative stress inhibition and autophagy promotion in high glucose and contrast media treatments-induced human kidney-2 (HK-2) cells.
Conclusion
PUM2 overexpression suppressed oxidative stress and promoted autophagy to alleviate renal injury in DM-CIAKI through interacting with HDAC9 mRNA, which mediated degradation of HDAC9 mRNA and inhibition of HDAC9 expression.

Citations

Citations to this article as recorded by

Purpurin Rescues Contrast-Induced Acute Rat Kidney Injury via Inducing Autophagy and Inhibiting Apoptosis
Kangxu He, Xiaoying Sun, Xinhui Pan, Xiaoda Yang, Qi Wang, Kai Liao
Pharmaceuticals.2026; 19(1): 116. CrossRef
Rubia cordifolia L. Dichloromethane Extract Ameliorates Contrast-Induced Acute Kidney Injury by Activating Autophagy via the LC3B/p62 Axis
Xiaoying Sun, Kangxu He, Guanzhong Chen, Xiaoda Yang, Xinhui Pan, Kai Liao
Molecules.2026; 31(2): 316. CrossRef

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

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