Following ischemic renal injury (IRI), selective proximal straight tubule (PST) injury occurs in in vivoexperimental models. Previous reports indicated that selective glycolytic inhibition and theconsequent ATP depletion is the initiating cause that triggers all the subsequent events leading toPST injury and cell death to instigate renal dysfunction; however, the exact mechanism by whichglycolysis is inhibited is not elucidated. Our recent report demonstrates that poly (ADP-ribose)Polymerase-1 (PARP-1) mediated inhibition of the key glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), can induce downregulation of glycolysis and ATP depletion inIRI. However, GAPDH inhibition by PARP-1 only partially accounted for ATP depletion, suggestingthat synergetic inhibition at additional glycolytic steps may occur. The current proposal is based onnew preliminary data indicating a novel paradigm that links p53 target TIGAR (Tp53 inducibleglycolysis and apoptosis regulator) to metabolic regulation of the rate limiting glycolytic enzymePhosphofructokinase (PFK) to induce ATP depletion and PST injury post-IRI. The objective of theproposal is to define the role and the mechanisms by which TIGAR regulate glycolytic energymetabolism in ischemic renal PST and determine whether synergistic inhibition of TIGAR and PARP-1 protects from glycolytic inhibition and ATP depletion in the setting of IRI. The central hypothesisis that modulation of the activity of the key glycolytic enzymes, PFK and GAPDH by TIGAR andPARP-1 respectively, leads to downregulation of glycolysis and anaerobic ATP production in ischemicPSTs. Based on our strong preliminary data, the validity of the hypothesis will be tested by pursuingthe following three specific aims: 1) determine the mechanism by which TIGAR activation in renalPSTs inhibits anaerobic energy production post-IRI; 2) determine if the level of ischemic stress switchTIGAR response towards ROS scavenging and autophagy versus glycolytic inhibition and cell deathpathways post-IRI and 3) determine if synergetic inhibition of TIGAR and PARP activation completelyprotects PST from ischemic/hypoxic injury in in vivo models. Successful completion of the proposedstudies, will establish a new paradigm on the role of PARP-1 and TIGAR as the primary mechanismthat initiates glycolytic inhibition, ATP depletion and PST injury in IRI. The studies are innovative asa role for PARP-1 and TIGAR in glycolytic inhibition in a pathological condition such asischemia/reperfusion injury has not been previously addressed in any organ. Results from the studymay provide novel therapeutic opportunities to intervene in PARP-1 and TIGAR functions to modulatePST injury at its onset and may be extrapolated to intervene in the pathogenesis of human AKI.
Acute kidney injury (AKI) is a devastating clinical syndrome with high mortality rate. Currently, no clinically- approved methods are available to treat or reverse the disease. Successful completion of the proposed project may ultimately provide novel therapeutic opportunities to intervene in PARP-1 and TIGAR functions to modulate the pathogenesis of human AKI, which could substantially reduce the morbidity and mortality and reduce the health care cost associated with AKI.
| Ying, Yuan; Padanilam, Babu J (2016) Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis? Cell Mol Life Sci 73:2309-24 |
| Kim, Jinu; Devalaraja-Narashimha, Kishor; Padanilam, Babu J (2015) TIGAR regulates glycolysis in ischemic kidney proximal tubules. Am J Physiol Renal Physiol 308:F298-308 |
| Kim, Jinu; Padanilam, Babu J (2015) Renal denervation prevents long-term sequelae of ischemic renal injury. Kidney Int 87:350-8 |
| Kim, Jinu; Padanilam, Babu J (2013) Renal nerves drive interstitial fibrogenesis in obstructive nephropathy. J Am Soc Nephrol 24:229-42 |
