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Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
Published on: November 21, 2025
TIGAR regulates glycolysis in ischemic kidney proximal tubules
Jinu Kim1, Kishor Devalaraja-Narashimha2, Babu J Padanilam3
1Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; Department of Anatomy, Jeju National University School of Medicine, Jeju, Republic of Korea; Department of Biomedicine and Drug Development, Jeju National University, Jeju, Republic of Korea; and.
Abstract:
Tp53-induced glycolysis and apoptosis regulator (TIGAR) activation blocks glycolytic ATP synthesis by inhibiting phosphofructokinase-1 activity. Our data indicate that TIGAR is selectively induced and activated in renal outermedullary proximal straight tubules (PSTs) after ischemia-reperfusion injury in a p53-dependent manner. Under severe ischemic conditions, TIGAR expression persisted through 48 h postinjury and induced loss of renal function and histological damage. Furthermore, TIGAR upregulation inhibited phosphofructokinase-1 activity, glucose 6-phosphate dehydrogenase (G6PD) activity, and induced ATP depletion, oxidative stress, autophagy, and apoptosis. Small interfering RNA-mediated TIGAR inhibition prevented the aforementioned malevolent effects and protected the kidneys from functional and histological damage. After mild ischemia, but not severe ischemia, G6PD activity and NADPH levels were restored, suggesting that TIGAR activation may redirect the glycolytic pathway into gluconeogenesis or the pentose phosphate pathway to produce NADPH. The increased level of NADPH maintained the level of GSH to scavenge ROS, resulting in a lower sensitivity of PST cells to injury. Under severe ischemia, G6PD activity and NADPH levels were reduced during reperfusion; however, blockade of TIGAR enhanced their levels and reduced oxidative stress and apoptosis. Collectively, these results demonstrate that inhibition of TIGAR may protect PST cells from energy depletion and apoptotic cell death in the setting of severe ischemia-reperfusion injury. However, under low ischemic burden, TIGAR activation induces the pentose phosphate pathway and autophagy as a protective mechanism.
Insights
Tp53-induced glycolysis and apoptosis regulator (TIGAR) activation in kidney tubules worsens injury after severe ischemia. Inhibiting TIGAR protects kidneys by preventing energy depletion and cell death, while mild ischemia benefits from TIGAR activation.
Area of Science:
- Biochemistry
- Cell Biology
- Renal Physiology
Background:
- Ischemia-reperfusion injury (IRI) significantly impacts kidney function, particularly in proximal straight tubules (PSTs).
- The role of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in renal IRI is not fully understood.
- Understanding TIGAR's dual role in different injury severities is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of TIGAR in p53-dependent renal IRI.
- To elucidate the mechanisms by which TIGAR influences cellular metabolism and survival under varying ischemic conditions.
- To determine the therapeutic potential of TIGAR inhibition in protecting against renal damage.
Main Methods:
- TIGAR expression and activity were analyzed in PSTs following IRI.
- Inhibition of TIGAR was achieved using small interfering RNA (siRNA).
- Metabolic parameters including ATP levels, phosphofructokinase-1, G6PD activity, and NADPH levels were measured.
- Assessment of oxidative stress, autophagy, apoptosis, renal function, and histological damage was performed.
Main Results:
- TIGAR was selectively induced in PSTs post-IRI in a p53-dependent manner.
- Severe ischemia led to persistent TIGAR upregulation, inhibiting key glycolytic enzymes, depleting ATP, increasing oxidative stress, and promoting apoptosis, resulting in renal dysfunction.
- TIGAR inhibition via siRNA ameliorated these detrimental effects and protected kidney function and histology.
- Mild ischemia showed TIGAR activation redirecting metabolism to the pentose phosphate pathway, enhancing NADPH production, reducing oxidative stress, and conferring protection.
Conclusions:
- TIGAR inhibition is a promising strategy to protect PSTs from energy depletion and apoptosis during severe renal IRI.
- TIGAR activation serves a protective role under mild ischemic conditions by promoting NADPH production and mitigating oxidative stress.
- The contrasting effects of TIGAR in mild versus severe IRI highlight its complex role in renal pathophysiology.
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