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J Am Soc Nephrol. 2016 Sep 9. pii: ASN.2016010012. [Epub ahead of print]

Targeting eIF5A Hypusination Prevents Anoxic Cell Death through Mitochondrial Silencing and Improves Kidney Transplant Outcome.

Author information

  • 1Laboratoire de Physio-Médecine Moléculaire, Centre National de la Recherche Scientifique-UMR7370.
  • 2Centre Hospitalo Universitaire Poitiers, Service de Biochimie, Poitiers, France; Institut National de la Santé et de la Recherche Médicale U1082 Ischémie Reperfusion en Transplantation d'Organes Mécanismes et Innovations Thérapeutiques, Poitiers, France; Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France; and.
  • 3Institut de Recherche sur le Cancer, Centre National de la Recherche Scientifique-UMR7284, Institut National de la Santé et de la Recherche Médicale U1081.
  • 4Institute of Biology Valrose, Centre National de la Recherche Scientifique-UMR7277 Institut National de la Santé et de la Recherche Médicale U1091.
  • 5Department of Radiation Oncology, University of Tübingen, Tuebingen, Germany.
  • 6Centre Commun de Microscopie Appliquée, and.
  • 7Institut de Physiologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Mixte de Recherche UMR7275, University Nice-Sophia Antipolis, Nice, France;
  • 8Laboratoire de Physio-Médecine Moléculaire, Centre National de la Recherche Scientifique-UMR7370, michel.tauc@unice.fr.

Abstract

The eukaryotic initiation factor 5A (eIF5A), which is highly conserved throughout evolution, has the unique characteristic of post-translational activation through hypusination. This modification is catalyzed by two enzymatic steps involving deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Notably, eIF5A may be involved in regulating the lifespan of Drosophila during long-term hypoxia. Therefore, we investigated the possibility of a link between eIF5A hypusination and cellular resistance to hypoxia/anoxia. Pharmacologic targeting of DHPS by N1-guanyl-1,7-diaminoheptane (GC7) or RNA interference-mediated inhibition of DHPS or DOHH induced tolerance to anoxia in immortalized mouse renal proximal cells. Furthermore, GC7 treatment of cells reversibly induced a metabolic shift toward glycolysis as well as mitochondrial remodeling and led to downregulated expression and activity of respiratory chain complexes, features characteristic of mitochondrial silencing. GC7 treatment also attenuated anoxia-induced generation of reactive oxygen species in these cells and in normoxic conditions, decreased the mitochondrial oxygen consumption rate of cultured cells and mice. In rats, intraperitoneal injection of GC7 substantially reduced renal levels of hypusinated eIF5A and protected against ischemia-reperfusion-induced renal injury. Finally, in the preclinical pig kidney transplant model, intravenous injection of GC7 before kidney removal significantly improved graft function recovery and late graft function and reduced interstitial fibrosis after transplant. This unconventional signaling pathway offers an innovative therapeutic target for treating hypoxic-ischemic human diseases and organ transplantation.

KEYWORDS:

cell survival; hypoxia; ischemia; kidney transplantation; renal cell biology; transplant outcomes

PMID:
27612998
DOI:
10.1681/ASN.2016010012
[PubMed - as supplied by publisher]
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