title: Treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates ischemic acute kidney injury.
abstract: BACKGROUND
  Hypoxia-inducible factor (HIF) transcriptional system plays a central role in cellular adaptation to low oxygen levels. Preconditional activation of HIF and/or expression of its individual target gene products leading to cytoprotection have been well established in hypoxic/ischemic renal injury. Increasing evidence indicate HIF activation is involved in hypoxic/ischemic postconditioning of heart, brain and kidney. Very few studies evaluated the potential benefits of postischemia HIF activation in renal injury employing a pharmacological agent. We hypothesized that postischemia augmentation of HIF activation with a pharmacological agent would protect renal ischemia/reperfusion injury. For this, TRC160334, a novel HIF hydroxylase inhibitor, was used.
  
  
  METHODS
  TRC160334, a novel HIF hydroxylase inhibitor, was synthesized. Ability of TRC160334 for stabilization of HIF-α and consequent HIF activation was evaluated in Hep3B cells. Efficacy of TRC160334 was evaluated in a rat model of ischemia/reperfusion-induced AKI. Two different treatment protocols were employed, one involved treatment with TRC160334 before onset of ischemia, the other involved treatment after the reperfusion of kidneys.
  
  
  RESULTS
  TRC160334 treatment results in stabilization of HIF-α leading to HIF activation in Hep3B cells. Significant reduction in renal injury was observed by both treatment protocols and remarkable reduction in serum creatinine (23 and 71% at 24 and 48 h, respectively, p < 0.01) was observed with TRC160334 treatment applied after reperfusion. Urine output was significantly improved up to 24 h by both treatment protocols.
  
  
  CONCLUSIONS
  The data presented here provide pharmacologic evidence for postischemia augmentation of HIF activation by TRC160334 as a promising and clinically feasible strategy for the treatment of renal ischemia/reperfusion injury.
authors.affiliation: Torrent Research Centre, Torrent Pharmaceuticals Ltd., Gandhinagar, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Jamadarkhana
authors.forename: Anita
authors.initials: A
authors.lastname: Chaudhary
authors.forename: Laxmikant
authors.initials: L
authors.lastname: Chhipa
authors.forename: Amita
authors.initials: A
authors.lastname: Dubey
authors.forename: Anookh
authors.initials: A
authors.lastname: Mohanan
authors.forename: Rameshchandra
authors.initials: R
authors.lastname: Gupta
authors.forename: Shailesh
authors.initials: S
authors.lastname: Deshpande
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D000818:Animals; D045744:Cell Line, Tumor; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008297:Male; D008954:Models, Biological; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D013997:Time Factors
chemical_list: C578784:((2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H,5H-10-thia-1,4a-diazabenzo(a)azulene-3-carbonyl)amino)acetic acid; D006575:Heterocyclic Compounds, 3-Ring; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D003404:Creatinine; D011393:Procollagen-Proline Dioxygenase; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine