title: Expression of a soluble complement inhibitor protects transgenic mice from antibody-induced acute renal failure.
abstract: Crry is a potent complement regulator in rodents that inhibits C3 convertases. In rats, intrarenal arterial injection of anti-glomerular endothelial cell (GEN) antibodies leads to complement-dependent microvascular injury and acute renal failure. In this study, a mouse variant of this model and the effects of complement inhibition were examined. Transgenic mice that overexpressed soluble Crry systemically and in their kidneys were studied. Anti-GEN IgG was injected intravenously into eight Crry transgenic mice and seven transgene-negative littermates (which were used as control animals). Thirty h after injection, blood urea nitrogen (BUN) levels were 30.3 +/- 4.4 and 114.8 +/- 23.5 mg/dl for transgene-positive and -negative animals, respectively (P = 0.012). Four of five transgene-negative animals with BUN levels of > 100 mg/dl were anuric; the remaining animal exhibited minimal albuminuria and no detectable urinary C3. In animals with renal failure, glomerular capillary collapse and tubular necrosis were observed. There was significant tubular staining for C3 in transgene-negative animals, with cellular and basal distributions, both of which were statistically greater than those in transgene-positive animals. Tubular cell C3 staining was strongly correlated with BUN values (r = 0.83, P < 0.001), as was C9 staining (r = 0.56, P = 0.037), suggesting that complement activation to the C5b-9 membrane attack complex had a casual role in renal failure. Thus, systemic injection of anti-GEN antibodies into mice leads to acute renal failure, with glomerular and tubular injury. Animals that overexpress soluble Crry in renal tubules and elsewhere are protected from the acute renal failure that occurs in this model, which ultimately seems to develop because of complement activation focused on tubules.
authors.affiliation: Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schiller
authors.affiliation: Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Cunningham
authors.affiliation: Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
authors.forename: Jessy J
authors.initials: JJ
authors.lastname: Alexander
authors.affiliation: Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
authors.forename: Lihua
authors.initials: L
authors.lastname: Bao
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado.
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.affiliation: Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D015870:Gene Expression; D007678:Kidney Glomerulus / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011951:Receptors, Complement / Q000235:genetics*; D017463:Receptors, Complement 3b; D012995:Solubility
chemical_list: D001323:Autoantibodies; D003176:Complement C3; D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D012333:RNA, Messenger; D011951:Receptors, Complement; D017463:Receptors, Complement 3b