Macrophages expressing heme oxygenase-1 improve renal function in ischemia/reperfusion injury.
Acute kidney injury has a high mortality and lacks specific therapies, with ischemia/reperfusion injury (IRI) being the predominant cause. Macrophages (M phi) have been used successfully in cell therapy to deliver targeted therapeutic genes in models of inflammatory kidney disease. Heme oxygenase-1 (HO-1) catalyzes heme breakdown and has important cytoprotective functions. We hypothesized that administration of M phi modified to overexpress HO-1 would protect from renal IRI. Using an adenoviral construct (Ad-HO-1), HO-1 was overexpressed in primary bone marrow-derived M phi (BMDM). In vitro Ad-HO-1 M phi showed an anti-inflammatory phenotype with increased phagocytosis of apoptotic cells (ACs) and increased interleukin (IL)-10 but reduced TNF-alpha and nitric oxide (NO) following lipopolysaccharide/interferon-gamma (IFN gamma) stimulation compared to control transduced or unmodified M phi. In vivo, intravenously (IV) injected M phi homed preferentially to the post-IRI kidney compared to uninjured control following experimental IRI. At 24 hours postinjury, despite equivalent levels of tubular necrosis, apoptosis, and capillary density between groups, the injection of Ad-HO-1 M phi resulted in preserved renal function (serum creatinine reduced by 46%), and reduced microvascular platelet deposition. These data demonstrate that genetically modified M phi improve the outcomes in IRI when administered after the establishment of structural injury, raising the prospect of targeted cell therapy to support the function of the acutely injured kidney.
Ferenbach
David A
DA
MRC Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, UK. dferenbach@hotmail.com
Ramdas
Vasudev
V
Spencer
Nishrin
N
Marson
Lorna
L
Anegon
Ignacio
I
Hughes
Jeremy
J
Kluth
David C
DC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D051547:Heme Oxygenase-1