Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure.
Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Normoxic degradation of HIF is mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative alpha-subunits by HIF prolyl hydroxylases (PHD). It was hypothesized that inhibition of HIF degradation by either hypoxia or pharmacologic inhibition of PHD would confer protection against subsequent ischemic injury. For testing this hypothesis ischemic acute renal failure was induced in rats by 40 min of clamping of the left renal artery after right-sided nephrectomy. Before surgery, pretreatment with either carbon monoxide, leading to tissue hypoxia, or the novel PHD inhibitor FG-4487 was applied. No toxic effects of FG-4487 were observed. Both pretreatments strongly induced the accumulation of HIF-1alpha and HIF-2alpha in tubular and peritubular cells, respectively, as well as HIF target gene expression. The course of subsequent ischemic injury was significantly ameliorated by both strategies of preconditioning, as evident from a significant improvement of serum creatinine and serum urea after 24 and 72 h. Furthermore, tissue injury and apoptosis were less severe, which were quantified by application of a standardized histologic scoring system in a blinded manner. In conclusion, the data provide proof of principle that preconditional activation of the HIF system protects against ischemic injury. Inhibiting the activity of HIF hydroxylases therefore seems to have considerable clinical perspectives.
Bernhardt
Wanja M
WM
Department of Nephrology and Hypertension, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Loschgestrasse, Erlangen, Germany. wanja.bernhardt@med4.imed.uni-erlangen.de
Câmpean
Valentina
V
Kany
Sarah
S
Jürgensen
Jan-Steffen
JS
Weidemann
Alexander
A
Warnecke
Christina
C
Arend
Michael
M
Klaus
Stephen
S
Günzler
Volkmar
V
Amann
Kerstin
K
Willam
Carsten
C
Wiesener
Michael S
MS
Eckardt
Kai-Uwe
KU
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002248:Carbon Monoxide / Q000008:administration & dosage*; D002460:Cell Line; D003404:Creatinine / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D011292:Premedication; D011393:Procollagen-Proline Dioxygenase / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D014508:Urea / Q000097:blood
D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002248:Carbon Monoxide; D014508:Urea; D003404:Creatinine; D011393:Procollagen-Proline Dioxygenase