TIGAR regulates glycolysis in ischemic kidney proximal tubules

Jinu Kim, Kishor Devalaraja-Narashimha, Babu J. Padanilam

Research output: Contribution to journalArticle

25 Scopus citations

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-rep-erfusion 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 gluconeo-genesis 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 au-tophagy as a protective mechanism.

Original languageEnglish (US)
Pages (from-to)F298-F308
JournalAmerican Journal of Physiology - Renal Physiology
Volume308
Issue number4
DOIs
StatePublished - 2015

Keywords

  • ATP depletion
  • Glycolytic inhibition
  • Ischemic renal injury
  • Phospho-fructokinase
  • Proximal straight tubules
  • Tp53-induced glycolysis and apoptosis regulator

ASJC Scopus subject areas

  • Physiology
  • Urology

Fingerprint Dive into the research topics of 'TIGAR regulates glycolysis in ischemic kidney proximal tubules'. Together they form a unique fingerprint.

  • Cite this