NDT Advance Access originally published online on November 29, 2007
Nephrology Dialysis Transplantation 2008 23(4):1135-1143; doi:10.1093/ndt/gfm808
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Evidence for sustained renal hypoxia and transient hypoxia adaptation in experimental rhabdomyolysis-induced acute kidney injury
1 Department of Nephrology and Medical Intensive Care, Charité Universitaetsmedizin, Berlin, Germany 2 Nephrology Unit, Bikur Holim Hospital 3 Hadassah University Hospital Mt. Scopus and the Hebrew Medical School, Jerusalem, Israel 4 Department of Anatomy, Humboldt University, Berlin 5 Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany 6 Department of Pathology, Charité Universitätsmedizin, Berlin, Germany 7 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
Christian Rosenberger, Nephrology and Medical Intensive Care, Charité Universitaetsmedizin, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49-30-450553232; Fax: +49-30-79741921; E-mail: chrosenbe{at}aol.com
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Abstract |
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Background. Indirect evidence suggests that hypoxia contributes to the pathophysiology of rhabdomyolysis-induced acute kidney injury (AKI). However, the cellular location and kinetics of hypoxia, as well as potential hypoxia adaptation are unclear.
Methods. Rhabdomyolysis was induced in rats by IM glycerol (GLY) injection, which largely recapitulates the full clinical syndrome. Additional rats received IV myoglobin (MYO), in order to assess the contribution of MYO per se. We performed immunohistochemistry for hypoxia markers [pimonidazole (PIM) adducts and hypoxia-inducible factors (HIFs)] and the cell-protective HIF target gene heme oxygenase-1 (HO-1). Furthermore, we sought a potential negative feedback loop to terminate HIF activation, driven by HIF prolyl-hydroxylase-2 (PHD-2).
Results. In GLY, progressive tubular injury, mainly of proximal tubules (PT), developed over time, but its extent was heterogeneous. PIM, HIF
and HO-1 were all absent in controls, but strongly positive in GLY, with a specific spatio-temporal pattern. In PT, (a) PIM was detectable throughout the study with a maximum at 6 h, (b) HIF was activated only at 3 h and (c) HO-1 and PHD-2 appeared at 6 h and persisted at a lower level at 24 h. Apart from tubular cast formation, MYO did not cause overt tissue damage, but led to strong activation of HIFs, in a pattern similar to 3 h of GLY.
Conclusions. Our data suggest that renal hypoxia occurs in rhabdomyolysis, and that MYO, at least partly, contributes to hypoxia generation. Since in the most affected tubules transcriptional hypoxia adaptation is transient and inhomogeneous, pharmacologic HIF enhancement holds the potential to improve outcome in rhabdomyolysis-induced AKI.
Keywords: acute renal failure; heme oxygenase-1; HIF prolyl hydroxylase-2; hypoxia-inducible factors; pimonidazole
Received for publication: 21. 8.07
Accepted in revised form: 16.10.07