title: 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.affiliation: Department 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.
authors.forename: Jinu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Kishor
authors.initials: K
authors.lastname: Devalaraja-Narashimha
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; Section of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska bpadanilam@unmc.edu.
authors.forename: Babu J
authors.initials: BJ
authors.lastname: Padanilam
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress; D010732:Phosphofructokinase-1 / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D009249:NADP; D000255:Adenosine Triphosphate; D005954:Glucosephosphate Dehydrogenase; D010732:Phosphofructokinase-1; D010744:Phosphoric Monoester Hydrolases; C554952:TIGAR protein, mouse; D005978:Glutathione
keywords: ATP depletion; Tp53-induced glycolysis and apoptosis regulator; glycolytic inhibition; ischemic renal injury; phosphofructokinase; proximal straight tubules