Evidence for sustained renal hypoxia and transient hypoxia adaptation in experimental rhabdomyolysis-induced acute kidney injury.
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, HIFalpha 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.
Christian Rosenberger, Nephrology and Medical Intensive Care, Charité Universitaetsmedizin, Augustenburger Platz 1, 13353 Berlin, Germany. chrosenbe@aol.com
Christian
C
Rosenberger
Marina
M
Goldfarb
Ahuva
A
Shina
Sebastian
S
Bachmann
Ulrich
U
Frei
Kai-Uwe
KU
Eckardt
Thomas
T
Schrader
Seymour
S
Rosen
Samuel N
SN
Heyman
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005990:Glycerol / Q000008:administration & dosage / Q000633:toxicity; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008297:Male; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity
D051793:Hypoxia-Inducible Factor 1; D012997:Solvents; D011393:Procollagen-Proline Dioxygenase; C580731:Egln1 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051547:Heme Oxygenase-1; D005990:Glycerol