TIGAR regulates glycolysis in ischemic kidney proximal tubules.

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.

• Authors: Jinu Kim, Kishor Devalaraja-Narashimha, Babu J Padanilam
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 308 Issue 4 Pg. F298-308 (Feb 15 2015) ISSN: 1522-1466 [Electronic] United States
• PMID: 25503731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• Apoptosis Regulatory Proteins
• Proteins
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• NADP
• Adenosine Triphosphate
• Glucosephosphate Dehydrogenase
• Phosphofructokinase-1
• Phosphoric Monoester Hydrolases
• TIGAR protein, mouse
• Glutathione

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis
• Apoptosis Regulatory Proteins
• Autophagy
• Cells, Cultured
• Disease Models, Animal
• Glucosephosphate Dehydrogenase (metabolism)
• Glutathione (metabolism)
• Glycolysis
• Injections, Intravenous
• Kidney Diseases (genetics, metabolism, pathology)
• Kidney Tubules, Proximal (metabolism, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• NADP (metabolism)
• Oxidative Stress
• Phosphofructokinase-1 (metabolism)
• Phosphoric Monoester Hydrolases
• Proteins (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (administration & dosage)
• Reperfusion Injury (genetics, metabolism, pathology)
• Severity of Illness Index
• Time Factors
• Tumor Suppressor Protein p53 (deficiency, genetics)