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Updated: Jun 21, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
PDK4-mediated Nrf2 inactivation contributes to oxidative stress and diabetic kidney injury
Shasha Tian1, Xiaopeng Yang1, Yao Lin1
1NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China; Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China.
Abstract:
Diabetic kidney disease (DKD) is often featured with redox dyshomeostatis. Pyruvate dehydrogenase kinase 4 (PDK4) is the hub for DKD development. However, the mechanism by which PDK4 mediates DKD is poorly understood. The current work aimed to elucidate the relationship between PDK4 and DKD from the perspective of redox manipulation. Oxidative stress was observed in the human proximal tubular cell line (HK-2 cells) treated with a high concentration of glucose and palmitic acid (HGL). The mechanistic study showed that PDK4 could upregulate Kelch-like ECH-associated protein 1 (Keap1) in HGL-treated HK-2 cells through the suppression of autophagy, resulting in the depletion of nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of redox homeostasis. At the cellular level, pharmacological inhibition or genetic knockdown of PDK4 could boost Nrf2, followed by the increase of a plethora of antioxidant enzymes and ferroptosis-suppression enzymes. Meanwhile, the inhibition or knockdown of PDK4 remodeled iron metabolism, further mitigating oxidative stress and lipid peroxidation. The same trend was observed in the DKD mice model. The current work highlighted the role of PDK4 in the development of DKD and suggested that PDK4 might be a promising target for the management of DKD.
Insights
Pyruvate dehydrogenase kinase 4 (PDK4) drives diabetic kidney disease (DKD) by disrupting redox balance. Inhibiting PDK4 restores the master antioxidant Nrf2, offering a potential therapeutic strategy for DKD.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Diabetic kidney disease (DKD) is characterized by redox imbalance.
- Pyruvate dehydrogenase kinase 4 (PDK4) plays a key role in DKD pathogenesis.
- The precise mechanisms linking PDK4 to DKD remain unclear.
Purpose of the Study:
- To investigate the role of PDK4 in DKD through the lens of redox regulation.
- To elucidate the molecular mechanisms by which PDK4 influences redox homeostasis in DKD.
Main Methods:
- Utilized human proximal tubular (HK-2) cells exposed to high glucose and palmitic acid (HGL) to model DKD.
- Investigated PDK4's effect on Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways.
- Employed pharmacological inhibition and genetic knockdown of PDK4 in cellular and mouse models.
- Assessed changes in antioxidant enzymes, ferroptosis suppressors, and iron metabolism.
Main Results:
- HGL-induced oxidative stress in HK-2 cells.
- PDK4 upregulated Keap1 via autophagy suppression, leading to Nrf2 depletion in HGL-treated cells.
- PDK4 inhibition or knockdown restored Nrf2, increased antioxidant and ferroptosis-suppression enzymes.
- PDK4 modulation improved iron metabolism, reducing oxidative stress and lipid peroxidation in vitro and in vivo (DKD mice).
Conclusions:
- PDK4 is a critical mediator of redox dysregulation in DKD.
- Targeting PDK4 can enhance the Nrf2 antioxidant pathway and mitigate DKD progression.
- PDK4 represents a potential therapeutic target for managing diabetic kidney disease.
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