PMID- 21742784
OWN - NLM
STAT- MEDLINE
DCOM- 20120914
LR  - 20161125
IS  - 1460-2385 (Electronic)
IS  - 0931-0509 (Linking)
VI  - 27
IP  - 3
DP  - 2012 Mar
TI  - The protective effect of prolyl-hydroxylase inhibition against renal ischaemia 
      requires application prior to ischaemia but is superior to EPO treatment.
PG  - 929-36
LID - 10.1093/ndt/gfr379 [doi]
AB  - 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-1alpha and -2alpha 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. 
      CONCLUSION: 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.
FAU - Wang, Zhendi
AU  - Wang Z
AD  - Department of Nephrology and Hypertension, Friedrich-Alexander-University 
      Erlangen-Nuremberg, Erlangen, Germany.
FAU - Schley, Gunnar
AU  - Schley G
FAU - Turkoglu, Gazi
AU  - Turkoglu G
FAU - Burzlaff, Nicolai
AU  - Burzlaff N
FAU - Amann, Kerstin U
AU  - Amann KU
FAU - Willam, Carsten
AU  - Willam C
FAU - Eckardt, Kai-Uwe
AU  - Eckardt KU
FAU - Bernhardt, Wanja M
AU  - Bernhardt WM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110708
PL  - England
TA  - Nephrol Dial Transplant
JT  - Nephrology, dialysis, transplantation : official publication of the European 
      Dialysis and Transplant Association - European Renal Association
JID - 8706402
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - 11096-26-7 (Erythropoietin)
RN  - 64FS3BFH5W (Epoetin Alfa)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
SB  - IM
MH  - Acute Kidney Injury/metabolism/pathology/*prevention & control
MH  - Animals
MH  - Enzyme Inhibitors/pharmacology
MH  - Epoetin Alfa
MH  - Erythropoietin/*therapeutic use
MH  - Hypoxia/drug therapy
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Immunoenzyme Techniques
MH  - Male
MH  - Procollagen-Proline Dioxygenase/*antagonists & inhibitors
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Real-Time Polymerase Chain Reaction
MH  - Recombinant Proteins/therapeutic use
MH  - Reperfusion Injury/metabolism/pathology/*prevention & control
EDAT- 2011/07/12 06:00
MHDA- 2012/09/15 06:00
CRDT- 2011/07/12 06:00
PHST- 2011/07/12 06:00 [entrez]
PHST- 2011/07/12 06:00 [pubmed]
PHST- 2012/09/15 06:00 [medline]
AID - gfr379 [pii]
AID - 10.1093/ndt/gfr379 [doi]
PST - ppublish
SO  - Nephrol Dial Transplant. 2012 Mar;27(3):929-36. doi: 10.1093/ndt/gfr379. Epub 
      2011 Jul 8.