Scientific RepoRts | 7: 197 | DOI:10.1038/s41598-017-00220-w
Specic expression of heme
oxygenase-1 by myeloid cells
modulates renal ischemia-
, Antoine Thierry
, Sandrine Delbauve
, Nicolas Preyat
, Miguel P. Soares
, Thierry Roumeguère
, Oberdan Leo
, Véronique Flamand
, Alain Le Moine
Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal
transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1
(HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly
characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1
), littermate (LT), and wild-
type (WT) mice were subjected to renal IRI or sham procedures and sacriced after 24 hours or 7 days.
In comparison to LT, HO-1
exhibited signicant renal histological damage, pro-inammatory
responses and oxidative stress 24 hours after reperfusion. HO-1
mice also displayed impaired
tubular repair and increased renal brosis 7 days after IRI. In WT mice, HO-1 induction with hemin
specically upregulated HO-1 within the CD11b
subset of the renal myeloid cells. Prior
administration of hemin to renal IRI was associated with signicant increase of the renal HO-1
myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was
abolished in HO-1
mice. In conclusion, myeloid HO-1 appears as a critical protective pathway
against renal IRI and could be an interesting therapeutic target in renal transplantation.
Ischemia-reperfusion injury (IRI) is inherent to renal transplantation and leads to delayed gra function (DGF)
of transplanted kidneys from deceased donors in up to 20 to 50% of cases
. Later, DGF contributes to the
reduced longevity of the kidney allogras, notably because of a higher risk of acute and chronic rejection
Basically, IRI is a two-phase phenomenon, including ischemia in the donor and reperfusion injury in the recip-
ient. It combines major ischemia-induced cell stress, signicant burst of free radicals, and intense inammatory
immune responses that lead to extensive cell injury, necrosis, and late interstitial brosis of the kidney allogra
. Today, the increasing demand for renal allogras implies more frequent use of organs issued from extended
criteria donors and this change leads to an increased risk of DGF
. So far, there is no specic treatment of IRI
and a better understanding of underlying mechanisms might lead to a better prevention of DGF and successful
transplantations even with transplant from extended criteria donors.
Several natural cellular mechanisms can confer resistance against IRI, including the ubiquitous heme oxy-
genase (HO) cytoprotective pathway
. Upon cellular stress, the expression of HO isoform 1 (HO-1, encoded by
Hmox1) is signicantly induced. e main action of HO-1 is the enzymatic degradation of free heme, a source of
reactive species massively released during IRI. HO-1 metabolizes free heme into carbon monoxide, biliverdin that
can both provide resistance against IRI
. Interestingly, HO-1-decient mice exhibit severe acute kidney injury
(AKI) and death upon renal IRI
. In humans, reduced capacity of the donor to express HO-1 was associated
Institute for Medical Immunology (IMI), Université Libre de Bruxelles, Gosselies, Belgium.
Department of Urology,
Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
Department of Nephrology, Dialysis and Renal
Transplantation, CHU de Poitiers, Poitiers, France.
Laboratory of Immunobiology, Institute for Molecular Biology
and Medicine, Université Libre de Bruxelles, Gosselies, Belgium.
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Department of Nephrology, Dialysis and Renal Transplantation, Hôpital Erasme, Université Libre de Bruxelles,
Brussels, Belgium. Alain Le Moine and Jean-Michel Hougardy jointly supervised this work. Correspondence and
requests for materials should be addressed to M.R. (email: email@example.com) or J.-M.H. (email: Jean-Michel.
Received: 17 October 2016
Accepted: 14 February 2017
Published: xx xx xxxx