Heme Oxygenase 1 Up-Regulates Glomerular Decay Accelerating Factor Expression and Minimizes Complement Deposition and Injury.
Complement-activation controllers, including decay accelerating factor (DAF), are gaining emphasis as they minimize injury in various dysregulated complement-activation disorders, including glomerulopathies. Heme oxygenase (HO)-1 overexpression or induction has been shown to attenuate injury in complement-dependent models of glomerulonephritis. This study investigated whether up-regulation of DAF by heme oxygenase 1 (HO-1) is an underlying mechanism by using Hmox-1-deficient rats (Hmox1+/-; Hmox1-/-) or rats with HO-1 overexpression targeted to glomerular epithelial cells (GECHO-1), which are particularly vulnerable to complement-mediated injury owing to their terminally differentiated nature. Constitutively expressed DAF was decreased in glomeruli of Hmox1-/-rats and augmented in glomeruli of GECHO-1rats. In GECHO-1rats with anti-glomerular basement membrane antibody mediated, complement-dependent injury, complement component C3 fragment b (C3b) deposition was reduced, whereas proteinuria was diminished. In glomeruli of wild-type rats, the natural Hmox substrate, hemin, induced glomerular DAF. This effect was attenuated in glomeruli of Hmox1-/-rats and augmented in glomeruli of GECHO-1rats. Hemin analogues differing in either metal or porphyrin ring functionalities, acting as competitive Hmox-substrate inhibitors, also increased glomerular DAF and reduced C3b deposition after spontaneous complement activation. In the presence of a DAF-blocking antibody, the reduction in C3b deposition was reversed. These observations establish HO-1 as a physiologic regulator of glomerular DAF and identify hemin analogues as inducers of functional glomerular DAF able to minimize C3b deposition.
First Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University School of Medicine, Athens, Greece. Electronic address: mdetsika@med.uoa.gr.
Maria G
MG
Detsika
Division of Nephrology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Pu
P
Duann
First Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University School of Medicine, Athens, Greece.
Vassilios
V
Atsaves
Research and Experimental Centre, ELPEN Pharmaceuticals, Athens, Greece.
Apostolos
A
Papalois
First Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University School of Medicine, Athens, Greece; Division of Nephrology, Department of Medicine, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Elias A
EA
Lianos
D000818:Animals; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation; D003179:Complement C3b / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005921:Glomerulonephritis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000031:analogs & derivatives / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011507:Proteinuria; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D018958:CD55 Antigens; D006427:Hemin; D003179:Complement C3b; D051547:Heme Oxygenase-1