title: The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment.
abstract: BACKGROUND
  Inhibition of the HIF regulating prolyl hydroxylation domain (PHDs) proteins prior to renal injury (preconditioning) has been shown to protect the kidney via activation of hypoxia-inducible transcription factors (HIF). Application of erythropoietin (EPO), one of the HIF target genes, has also been shown to be nephroprotective, and it remains unclear to what extent the effect of HIF induction is mediated by EPO. It is also unknown whether HIF activation after the onset of ischaemia (postconditioning) is still able to protect the kidney.
  
  
  METHODS
  Using a rat model of renal ischaemia-reperfusion injury, animals were treated with the PHD inhibitor (PHD-I) 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), vehicle (Veh) or recombinant human EPO (300 IU/kg) 6 h (ICA or Veh) or 30 min (EPO) prior to ischaemia (preconditioning) or with ICA prior to reperfusion (postconditioning). Renal function was assessed at baseline, 24 h and 72 h. After 72 h, kidneys were processed for histology and morphometric analysis. HIF immunohistochemistry and real-time polymerase chain reaction for HIF target genes, including EPO, were performed to evaluate ICA effects.
  
  
  RESULTS
  ICA treatment resulted in stabilization of HIF-1α and -2α and up-regulation of HIF target genes in a dose-dependent manner. Preconditional activation of HIF by ICA significantly improved serum creatinine levels and renal morphology in comparison to Veh (P < 0.05), while postconditional ICA treatment was ineffective. EPO therapy improved tissue morphology but had no impact on the course of serum creatinine.
  
  
  CONCLUSIONS
  These findings are in line with the concept that PHD-Is exert their protective effects through accumulation of HIF target gene products, with time requirements for increased transcription and translation of HIF-dependent genes, and suggest that their renoprotective effect is not predominately mediated by EPO.
authors: Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors: Zhendi
authors: Z
authors: Wang
authors: Gunnar
authors: G
authors: Schley
authors: Gazi
authors: G
authors: Türkoglu
authors: Nicolai
authors: N
authors: Burzlaff
authors: Kerstin U
authors: KU
authors: Amann
authors: Carsten
authors: C
authors: Willam
authors: Kai-Uwe
authors: KU
authors: Eckardt
authors: Wanja M
authors: WM
authors: Bernhardt
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000627:therapeutic use*; D000860:Hypoxia / Q000188:drug therapy; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D011393:Procollagen-Proline Dioxygenase