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Preconditional Activation of Hypoxia-Inducible Factors Ameliorates Ischemic Acute Renal Failure

Wanja M. Bernhardt^*, Valentina Câmpean, Sarah Kany, Jan-Steffen Jürgensen, Alexander Weidemann^*, Christina Warnecke^*, Michael Arend, Stephen Klaus, Volkmar Günzler, Kerstin Amann, Carsten Willam^*, Michael S. Wiesener^*,|| and Kai-Uwe Eckardt^*

Departments of ^* Nephrology and Hypertension and Pathology and ^|| IZKF, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, and Department of Nephrology and Medical Intensive Care, Charité, University Medicine Berlin, Berlin, Germany; and FibroGen Inc., South San Francisco, California

Address correspondence to: Dr. Wanja M. Bernhardt, Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Loschgestrasse 8, D-91054, Erlangen, Germany. Phone: +49-9131-8539002; Fax: +49-9131-8539209; E-mail: wanja.bernhardt{at}med4.imed.uni-erlangen.de

Received for publication December 15, 2005. Accepted for publication April 24, 2006.

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 -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-1 and HIF-2 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.

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