Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model

Bernhardt WM, Gottmann U, Doyon F, Buchholz B, Campean V, Schödel J, Reisenbuechler A, Klaus S, Arend M, Flippin L, Willam C, Yard B, Warnecke C, Eckardt KU, Wiesener M (2009)

Publication Status: Published

Publication Type: Journal article

Publication year: 2009

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Publisher: NATL ACAD SCIENCES

Book Volume: 106

Pages Range: 21276-21281

Journal Issue: 50

DOI: 10.1073/pnas.0903978106

Abstract

Long-term survival of renal allografts depends on the chronic immune response and is probably influenced by the initial injury caused by ischemia and reperfusion. Hypoxia-inducible transcription factors (HIFs) are essential for adaptation to low oxygen. Normoxic inactivation of HIFs is regulated by oxygen-dependent hydroxylation of specific prolyl-residues by prolyl-hydroxylases (PHDs). Pharmacological inhibition of PHDs results in HIF accumulation with subsequent activation of tissue-protective genes. We examined the effect of donor treatment with a specific PHD inhibitor (FG-4497) on graft function in the Fisher-Lewis rat model of allogenic kidney transplantation (KTx). Orthotopic transplantation of the left donor kidney was performed after 24 h of cold storage. The right kidney was removed at the time of KTx (acute model) or at day 10 (chronic model). Donor animals received a single dose of FG-4497 (40 mg/kg i.v.) or vehicle 6 h before donor nephrectomy. Recipients were followed up for 10 days (acute model) or 24 weeks (chronic model). Donor preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted beyond cold storage. It reduced acute renal injury (serum creatinine at day 10: 0.66 +/- 0.20 vs. 1.49 +/- 1.36 mg/dL; P < 0.05) and early mortality in the acute model and improved long-term survival of recipient animals in the chronic model (mortality at 24 weeks: 3 of 16 vs. 7 of 13 vehicle-treated animals; P < 0.05). In conclusion, pretreatment of organ donors with FG-4497 improves short-and long-term outcomes after allogenic KTx. Inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves clinical evaluation.

Authors with CRIS profile

Björn Buchholz Department of Medicine 4 – Nephrology and Hypertension Johannes Schödel Department of Medicine 4 – Nephrology and Hypertension Carsten Willam Department of Medicine 4 – Nephrology and Hypertension Christina Warnecke Department of Medicine 4 – Nephrology and Hypertension Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension Michael Wiesener Professur für Innere Medizin (Nephrologie)

Involved external institutions

FibroGen Inc. US United States (USA) (US) Universitätsklinikum Mannheim DE Germany (DE)

How to cite

APA:

Bernhardt, W.M., Gottmann, U., Doyon, F., Buchholz, B., Campean, V., Schödel, J.,... Wiesener, M. (2009). Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model. Proceedings of the National Academy of Sciences of the United States of America, 106(50), 21276-21281. https://doi.org/10.1073/pnas.0903978106

MLA:

Bernhardt, W. M., et al. "Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model." Proceedings of the National Academy of Sciences of the United States of America 106.50 (2009): 21276-21281.

BibTeX: Download