Heme Oxygenase 1 Up-Regulates Glomerular Decay Accelerating Factor Expression and Minimizes Complement Deposition and Injury

Am J Pathol. 2016 Nov;186(11):2833-2845. doi: 10.1016/j.ajpath.2016.07.009. Epub 2016 Sep 21.


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-1 rats. In GECHO-1 rats 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-1 rats. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD55 Antigens / genetics
  • CD55 Antigens / metabolism*
  • Complement Activation
  • Complement C3b / immunology
  • Complement C3b / metabolism
  • Disease Models, Animal
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Glomerulonephritis / enzymology
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Hemin / analogs & derivatives
  • Hemin / immunology*
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / injuries
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology
  • Male
  • Proteinuria
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation


  • CD55 Antigens
  • Hemin
  • Complement C3b
  • Heme Oxygenase-1