title: Partial Complement Factor H Deficiency Associates with C3 Glomerulopathy and Thrombotic Microangiopathy.
abstract: The complement-mediated renal diseases C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) strongly associate with inherited and acquired abnormalities in the regulation of the complement alternative pathway (AP). The major negative regulator of the AP is the plasma protein complement factor H (FH). Abnormalities in FH result in uncontrolled activation of C3 through the AP and associate with susceptibility to both C3G and aHUS. Although previously developed FH-deficient animal models have provided important insights into the mechanisms underlying susceptibility to these unique phenotypes, these models do not entirely reproduce the clinical observations. FH is predominantly synthesized in the liver. We generated mice with hepatocyte-specific FH deficiency and showed that these animals have reduced plasma FH levels with secondary reduction in plasma C3. Unlike mice with complete FH deficiency, hepatocyte-specific FH-deficient animals developed neither plasma C5 depletion nor accumulation of C3 along the glomerular basement membrane. In contrast, subtotal FH deficiency associated with mesangial C3 accumulation consistent with C3G. Although there was no evidence of spontaneous thrombotic microangiopathy, the hepatocyte-specific FH-deficient animals developed severe C5-dependent thrombotic microangiopathy after induction of complement activation within the kidney by accelerated serum nephrotoxic nephritis. Taken together, our data indicate that subtotal FH deficiency can give rise to either spontaneous C3G or aHUS after a complement-activating trigger within the kidney and that the latter is C5 dependent.
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Vernon
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
authors.forename: Marieta M
authors.initials: MM
authors.lastname: Ruseva
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom matthew.pickering@imperial.ac.uk.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
mesh_terms: D000818:Animals; D065766:Atypical Hemolytic Uremic Syndrome / Q000209:etiology*; D003167:Complement Activation; D003176:Complement C3; D017242:Complement Factor H / Q000172:deficiency*; D005260:Female; D000081208:Hereditary Complement Deficiency Diseases; D007668:Kidney / Q000098:blood supply; D007674:Kidney Diseases / Q000150:complications / Q000209:etiology*; D007678:Kidney Glomerulus; D008297:Male; D051379:Mice; D057049:Thrombotic Microangiopathies / Q000209:etiology*; D015432:Glomerulonephritis, Membranoproliferative
chemical_list: D003176:Complement C3; D017242:Complement Factor H
keywords: GN; complement; immunology; thrombosis; transgenic mouse