Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains

Abstract

C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh-/-) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH1-5) linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-P-FH1-5). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH1-5 to alter C3 activation in either plasma or glomeruli. Following IgG-FH1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh-/- mice IgG-FH1-5 reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH1-5 restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh-/- mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH1-5 protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy. C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh-/-) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH1-5) linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-P-FH1-5). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH1-5 to alter C3 activation in either plasma or glomeruli. Following IgG-FH1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh-/- mice IgG-FH1-5 reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH1-5 restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh-/- mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH1-5 protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy. Translational StatementC3 glomerulopathy (C3G) is a kidney disease characterized by abnormal accumulation of complement C3 within glomeruli and glomerular damage. It is due to uncontrolled activation of the complement alternative pathway. Fusion proteins, comprised of functional domains of the alternative pathway regulator, factor H (FH), linked to an antibody, restored complement regulation, and reduced glomerular C3 in a C3G mouse model. The non-targeting antibody conjugation resulted in a comparatively long fusion protein plasma half-life, and this, or similar conjugation methods, could be used to augment FH function in the therapy of C3G. C3 glomerulopathy (C3G) is a kidney disease characterized by abnormal accumulation of complement C3 within glomeruli and glomerular damage. It is due to uncontrolled activation of the complement alternative pathway. Fusion proteins, comprised of functional domains of the alternative pathway regulator, factor H (FH), linked to an antibody, restored complement regulation, and reduced glomerular C3 in a C3G mouse model. The non-targeting antibody conjugation resulted in a comparatively long fusion protein plasma half-life, and this, or similar conjugation methods, could be used to augment FH function in the therapy of C3G. C3 glomerulopathy (C3G) is a complement-mediated renal disorder characterized by abnormal amounts of C3 within glomeruli.1Fakhouri F. Frémeaux-Bacchi V. Noöl L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (258) Google Scholar It can progress to renal failure and has no definitive treatment.2Smith R.J.H. Appel G.B. Blom A.M. et al.C3 glomerulopathy—understanding a rare complement-driven renal disease.Nat Rev Nephrol. 2019; 15: 129-143Crossref PubMed Scopus (96) Google Scholar C3G is associated with abnormal activation of the complement alternative pathway (AP). AP activation results in the production of C3bBb (C3 convertase), an enzyme that cleaves C3. After the addition of another C3b molecule, the resulting C3bBbC3b complex (C5 convertase) can cleave complement C5. Uncontrolled AP activation in C3G can be associated with reduction in circulating C3, C5, factor B (FB), and properdin. Causes of uncontrolled AP activation include loss of function changes in complement regulators and gain of function changes in complement activators.2Smith R.J.H. Appel G.B. Blom A.M. et al.C3 glomerulopathy—understanding a rare complement-driven renal disease.Nat Rev Nephrol. 2019; 15: 129-143Crossref PubMed Scopus (96) Google Scholar The key negative AP regulator is factor H (FH), and FH deficiency in humans, pigs, and mice is associated with C3G.3Pickering M.C. Cook H.T. Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals.Clin Exp Immunol. 2008; 151: 210-230Crossref PubMed Scopus (144) Google Scholar C3 nephritic factor, an antibody that stabilizes the AP C3 convertase, is frequent in C3G.4Daha M.R. Fearon D.T. Austen K.F. C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase.J Immunol. 1976; 116: 1-7PubMed Google Scholar C3 nephritic factor may result in reduction in C3 alone (properdin-independent C3 nephritic factor) or reduction in both C3 and C5 (properdin-dependent C3 nephritic factor).5Mollnes T.E. Ng Y.C. Peters D.K. et al.Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro.Clin Exp Immunol. 1986; 65: 73-79PubMed Google Scholar,6Ng Y.C. Peters D.K. C3 nephritic factor (C3NeF): dissociation of cell-bound and fluid phase stabilization of alternative pathway C3 convertase.Clin Exp Immunol. 1986; 65: 450-457PubMed Google Scholar Restoring complement regulation should ameliorate C3G because C3 dysregulation is the central defect in pathogenesis. Accordingly, FH-deficient mice (Cfh–/–) did not develop spontaneous C3G if the mice were also deficient in FB.7Pickering M.C. Cook H.T. Warren J. et al.Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.Nat Genet. 2002; 31: 424-428Crossref PubMed Scopus (396) Google Scholar Properdin is a positive regulator of the AP C3 convertase, so its removal would be predicted to reduce C3 and C5 activation. In the Cfh–/– mouse strain, properdin deficiency unexpectedly exacerbated glomerular C3 deposition.8Lesher A.M. Zhou L. Kimura Y. et al.Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.J Am Soc Nephrol. 2013; 24: 53-65Crossref PubMed Scopus (64) Google Scholar,9Ruseva M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google Scholar Although properdin deficiency did not ameliorate plasma C3 levels, C5 levels increased, suggesting that properdin was necessary for the activity of the C5 but not C3 convertase.8Lesher A.M. Zhou L. Kimura Y. et al.Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.J Am Soc Nephrol. 2013; 24: 53-65Crossref PubMed Scopus (64) Google Scholar,9Ruseva M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google Scholar Administration of mouse10Paixao-Cavalcante D. Hanson S. Botto M. et al.Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase.Mol Immunol. 2009; 46: 1942-1950Crossref PubMed Scopus (37) Google Scholar or human FH11Fakhouri F. de Jorge E.G. Brune F. et al.Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.Kidney Int. 2010; 78: 279-286Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar,12Michelfelder S. Parsons J. Bohlender L.L. et al.Moss-produced, glycosylation-optimized human factor H for therapeutic application in complement disorders.J Am Soc Nephrol. 2017; 28: 1462-1474Crossref PubMed Scopus (23) Google Scholar to Cfh–/– mice reduced glomerular C3 staining and increased circulating C3 levels. Constructs that contain only the regulatory and targeting domains of FH (mini-FH molecules) are also efficacious in this model.13Nichols E.M. Barbour T.D. Pappworth I.Y. et al.An extended mini-complement factor H molecule ameliorates experimental C3 glomerulopathy.Kidney Int. 2015; 88: 1314-1322Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Other approaches include proteins that target sites of complement activation. These include TT30,14Ruseva M.M. Peng T. Lasaro M.A. et al.Efficacy of targeted complement inhibition in experimental C3 glomerulopathy.J Am Soc Nephrol. 2016; 27: 405-416Crossref PubMed Scopus (16) Google Scholar a protein containing the complement regulatory domains of FH (FH1-5) linked to the complement-binding domains of complement receptor 2, and homodimeric FH molecules,15Yang Y. Denton H. Davies O.R. et al.An engineered complement factor H construct for treatment of C3 glomerulopathy.J Am Soc Nephrol. 2018; 29: 1649-1661Crossref PubMed Scopus (22) Google Scholar mini-FH molecules that contain complement-binding domains of factor H–related protein 1. Because the therapeutic utility of inhibiting complement C3 activation is under investigation in C3G,2Smith R.J.H. Appel G.B. Blom A.M. et al.C3 glomerulopathy—understanding a rare complement-driven renal disease.Nat Rev Nephrol. 2019; 15: 129-143Crossref PubMed Scopus (96) Google Scholar it is important to understand the kinetics of glomerular C3 deposition and its relationship to AP activation within both glomeruli and the circulation. In models of immune complex–mediated glomerulonephritis, glomerular C3c cleared within 24 hours of preventing complement activation, whereas glomerular C3d persisted for weeks.16Schulze M. Pruchno C.J. Burns M. et al.Glomerular C3c localization indicates ongoing immune deposit formation and complement activation in experimental glomerulonephritis.Am J Pathol. 1993; 142: 179-187PubMed Google Scholar Similarly, in Cfh–/– mice, exogenous FH results in reduction in glomerular C3c staining at 24 hours, whereas glomerular C3d remains unchanged.11Fakhouri F. de Jorge E.G. Brune F. et al.Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.Kidney Int. 2010; 78: 279-286Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar In this study, we investigated the efficacy of 2 novel fusion proteins with complement regulatory activity in the Cfh–/– mouse model of C3G. The proteins contained the regulatory domains of mouse FH (FH1-5), which was conjugated to mouse Ig to prolong the biological half-life. One of the fusion proteins, termed IgG-FH1-5, was conjugated to a non-targeting mouse monoclonal antibody. The other, termed anti-P-FH1-5, was conjugated to a monoclonal antibody to mouse properdin. This was done to test the hypothesis that targeting this fusion protein to sites of complement activation, by interacting with properdin deposition, would enhance tissue complement regulation. Our data demonstrate that both the non-targeting (IgG-FH1-5) and the properdin-targeting (anti-P-FH1-5) proteins restored plasma and glomerular C3 regulation in Cfh–/– mice. Time course studies showed that restoration of C3 and FB levels mirrored levels of the fusion proteins in the circulation. In contrast, increases in plasma C5 persisted after the fusion proteins had cleared from the circulation. We show that IgG-FH1-5 ameliorated glomerular injury during accelerated serum nephrotoxic nephritis in Cfh–/– mice. Fusion proteins were created by linking the first 5 short consensus repeat (SCR) domains of mouse FH (FH1-5) to either an anti-mouse properdin antibody (anti-P-FH1-5) or an antibody with a non-targeting Ig domain (IgG-FH1-5, Supplementary Figure S1). The activity of the proteins was assessed an and IgG-FH1-5 in a with for also reduced in a but the had no After of the proteins Cfh–/– mice, the IgG-FH1-5 protein was to after whereas was to after Figure IgG-FH1-5 and could plasma AP regulation in Cfh–/– mice, we first plasma C3 levels after of the fusion proteins Administration of either IgG-FH1-5 or increased plasma C3 at 24 hours to a extent, at hours after These data that both IgG-FH1-5 and could plasma AP regulation in Cfh–/– mice. We a of changes by the course of changes in not only plasma C3 but also of plasma C5 and the alternative pathway proteins FB and properdin. We the kinetics of changes in C3, C5, and properdin by proteins at to after a of either IgG-FH1-5 or After of IgG-FH1-5, the in C3, C5, and properdin at The for changes to to levels The to levels and for and for C3, and and for both properdin and C5 and After of anti-P-FH1-5, C3 levels on but to levels and C5 levels on and to levels and The in FB on and to levels and plasma properdin was after of either or plasma properdin levels for to after and to after Although both fusion proteins restored plasma AP regulation, the of in C3, and C5 levels the of in which was for Figure In changes in the levels of C3 and FB after of either protein were than of C5 and properdin. These data that plasma FB is a sensitive marker of C3 convertase activity in this whereas properdin is a marker of C5 convertase Notably, after was a in C5 at 24 and hours and A.M. Zhou L. Kimura Y. et al.Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.J Am Soc Nephrol. 2013; 24: 53-65Crossref PubMed Scopus (64) Google Scholar,9Ruseva M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google Scholar this indicates that the C5 convertase is on properdin in Cfh–/– mice. We assessed the of IgG-FH1-5 and on glomerular and hours after of IgG-FH1-5, glomerular staining was reduced but glomerular C3d and staining was with either or The abnormal of glomerular properdin staining in Cfh–/– M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google Scholar hours after In Cfh–/– mice with either or IgG-FH1-5, the glomerular properdin was at hours resulted in a glomerular staining and This that the protein was in glomeruli. of protein mice resulted in glomerular staining with and at hours Figure that this with glomeruli. we that the protein could also with the glomerular properdin in Cfh–/– mice. we the Cfh–/– mice that had with to glomerular was a reduction in the staining and Figure These that the glomerular of protein in Cfh–/– mice is on glomerular properdin. In with renal injury can develop in the of loss of renal function in is associated with of Y. et C3 glomerulopathy associated with of in J Am Soc Nephrol. 6: PubMed Scopus Google Scholar The C3 dysregulation in C3G results in complement-mediated renal injury after a that results in renal model this, we accelerated serum nephrotoxic an glomerulonephritis model that complement and Y. F. et and in nephrotoxic nephritis is by of Exp PubMed Scopus Google T. M.C. et nephritis in and Exp Immunol. PubMed Scopus Google Scholar in the Cfh–/– mice. We showed that Cfh–/– mice are to renal injury in this M.C. Cook H.T. Warren J. et al.Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.Nat Genet. 2002; 31: 424-428Crossref PubMed Scopus (396) Google Scholar and that the FH1-5 protein, by AP regulation, could ameliorate complement-mediated renal injury in this model. Because our data that the protein was in we used IgG-FH1-5 during accelerated serum nephrotoxic nephritis. hours of nephrotoxic mice an of either or IgG-FH1-5 The experimental is in Figure were after of nephrotoxic of glomerular and were in the IgG-FH1-5 injury was also in the IgG-FH1-5 was in the but changes in serum and the did not glomerular was reduced in the IgG-FH1-5 but glomerular mouse and not did not the Both IgG-FH1-5 and C3, and C5 levels in Cfh–/– mice. This is with the that the complement regulatory domains of mouse FH are within domains through 5 and the activity for the factor of J. H. et of and C3b of mouse and human complement factor Immunol. PubMed Scopus Google Scholar which to and and include a are within domains through and are not in the fusion J. H. et of and C3b of mouse and human complement factor Immunol. PubMed Scopus Google Scholar both proteins reduced glomerular that was not required in this This is with data that Cfh–/– mice a FH protein of domains to did not develop abnormal glomerular C3 Jorge E.G. D. et of on complement Am Soc Nephrol. PubMed Scopus Google M.C. de Jorge E.G. et by complement factor H Exp PubMed Scopus Google Scholar were to C3 activation renal and It is to the of the targeting of fusion proteins containing FH1-5 in FH deficiency could result in to It is also that the increased for C3b by of the of the fusion proteins, is to for the of the targeting of C3b is also by changes in et by of factor H: for of from Immunol. 2015; PubMed Scopus Google Scholar protein which domain an FH and the complex had increased C3b and The is not in FH but in the This with C3d but FH de Jorge et of complement factor proteins complement activation in 2013; PubMed Scopus Google H. et of a immune with Immunol. 2013; PubMed Scopus Google Scholar We that our through may with both and Notably, both IgG-FH1-5 and from in an fusion protein reduced glomerular C3d because of the of glomerular In experimental glomerular C3c within 24 hours of of complement activation but C3d persisted for weeks.16Schulze M. Pruchno C.J. Burns M. et al.Glomerular C3c localization indicates ongoing immune deposit formation and complement activation in experimental glomerulonephritis.Am J Pathol. 1993; 142: 179-187PubMed Google Scholar In glomerular C3d is in et al.Glomerular complex is not a marker of ongoing C5 activation in Int. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar This its with glomerular of human FH in Cfh–/– mice did show a reduction in glomerular C3d a F. de Jorge E.G. Brune F. et al.Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.Kidney Int. 2010; 78: 279-286Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar It is that of IgG-FH1-5 reduce glomerular C3d in this model. was also no in glomerular is the of the mouse proteins, but are to with both J. F. et of the alternative pathway of complement by factor Immunol. 2018; PubMed Scopus Google M. et factor complement Immunol. 2017; PubMed Scopus Google Scholar and J. F. et of the alternative pathway of complement by factor Immunol. 2018; PubMed Scopus Google Scholar In the of both and for C3d is than that of J. F. et of the alternative pathway of complement by factor Immunol. 2018; PubMed Scopus Google Scholar We that glomerular proteins are to from glomeruli only C3d has In this it is that in human factor H–related protein 5 with glomerular H. et al.Glomerular complement factor protein 5 is in C3 glomerulopathy and associated with renal 2019; Full Text Full Text PDF PubMed Scopus Google Scholar The protein plasma properdin levels because the of this fusion protein can AP activity to properdin for after a T. S. D. et the alternative and ameliorates renal injury in factor and Immunol. 2013; PubMed Scopus Google Scholar our data showed that the efficacy of FH1-5 in plasma C3 levels and glomerular staining was the 2 fusion proteins was of properdin the abnormal glomerular properdin staining was reduced after of either or in to C3d and proteins, glomerular properdin is cleared after restoration of C3 regulation. properdin in after of the protein, but this was by the that we deposition of this fusion protein in both Cfh–/– and glomeruli. This was due to an with glomerular but the deposition in glomeruli it was also in of glomerular complement and to the of the fusion Our data novel with to the changes in C5, and properdin that increases in C3 in Cfh–/– mice after of the fusion FB levels rapidly after and to levels at a both C5 and properdin levels Properdin levels in Cfh–/– mice were reduced at and increased to levels after of IgG-FH1-5 and at levels for at similar course was for the in plasma C5 levels. IgG-FH1-5 was from the at that the formation of the C5 convertase in Cfh–/– mice is than that of the C3 convertase C3 levels to and C5 increased after treatment and increased with both properdin targeting and the of FH1-5 were to the increased C5 levels and that the C5 convertase is properdin in Cfh–/– mice. This is with of C5 dysregulation in mice with deficiency of FH and A.M. Zhou L. Kimura Y. et al.Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.J Am Soc Nephrol. 2013; 24: 53-65Crossref PubMed Scopus (64) Google Scholar,9Ruseva M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google Scholar properdin levels can be reduced in C3G and to with C5 convertase activity in to either plasma C5 or F. M. et properdin a of C5 convertase dysregulation in C3 Exp Immunol. 2016; PubMed Scopus Google Y. B. et the complement of C3 J Am Soc Nephrol. PubMed Scopus (53) Google Scholar Our data an properdin levels and C5 convertase activity and the of properdin levels a of ongoing glomerular C5 activation. Notably, the IgG-FH1-5 protein was in the to after a This is longer than we for the mouse FH1-5 protein, which was from the within 24 M.M. Peng T. Lasaro M.A. et al.Efficacy of targeted complement inhibition in experimental C3 glomerulopathy.J Am Soc Nephrol. 2016; 27: 405-416Crossref PubMed Scopus (16) Google Scholar This indicates that the longer plasma of the IgG-FH1-5 protein is from the antibody The plasma of the IgG-FH1-5 protein was also longer than we for D. Hanson S. Botto M. et al.Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase.Mol Immunol. 2009; 46: 1942-1950Crossref PubMed Scopus (37) Google F. de Jorge E.G. Brune F. et al.Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.Kidney Int. 2010; 78: 279-286Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar human FH was from the by hours after a in Cfh–/– F. de Jorge E.G. Brune F. et al.Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.Kidney Int. 2010; 78: 279-286Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar with our data the efficacy of the IgG-FH1-5 protein in complement regulation, we that conjugation of FH1-5 protein to prolong its has potential therapeutic utility in C3G. In we show the FH1-5 fusion proteins were in glomerular C3 activation and plasma complement regulation in FH deficiency. was no in the FH1-5 domains to and the IgG-FH1-5 protein reduced renal injury in experimental nephritis. In to the in of FH for therapeutic the production of is which this IgG-FH1-5 an potential therapeutic for C3G. The first 5 mouse FH domains linked to a non-targeting mouse Ig antibody a mouse monoclonal FH1-5 linked to mouse antibody T. S. D. et the alternative and ameliorates renal injury in factor and Immunol. 2013; PubMed Scopus Google Scholar to by of were non-targeting mouse Ig and mouse Figure S1). were and protein mouse serum from to was with at for was was serum with no was after of containing were by used were anti-mouse FH antibody and anti-mouse FB antibody was were with for and to the mice were in were to and by the mice were from and Cfh–/– mice were M.C. Cook H.T. Warren J. et al.Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.Nat Genet. 2002; 31: 424-428Crossref PubMed Scopus (396) Google Scholar were for and of proteins were for and for IgG-FH1-5 and serum nephrotoxic nephritis was by of nephrotoxic serum mice with M.C. Cook H.T. Warren J. et al.Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.Nat Genet. 2002; 31: 424-428Crossref PubMed Scopus (396) Google Scholar Administration of the fusion proteins was 24 hours nephrotoxic serum C3 was by M.M. Peng T. Lasaro M.A. et al.Efficacy of targeted complement inhibition in experimental C3 glomerulopathy.J Am Soc Nephrol. 2016; 27: 405-416Crossref PubMed Scopus (16) Google Scholar properdin and C5 levels were with or a C5 on properdin and C5 were with or monoclonal with The was a and was with properdin and C5 were used and were assessed plasma and kidney tissue M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google Scholar was on the and was by renal were assessed in a and to the of glomerular and injury 2 glomeruli were assessed to glomerular staining was on with used were anti-mouse M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google anti-mouse monoclonal mouse or properdin M.M. Vernon K.A. Lesher A.M. et al.Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency.J Am Soc Nephrol. 2013; 24: 43-52Crossref PubMed Scopus (53) Google Scholar anti-mouse C3d was used on with antibody FH was in anti-mouse FH and monoclonal antibody were anti-mouse was a with and glomeruli were and was in was used for of with test were and was used for the course The with test was used and was used for 2 has from and has from and and are of is a of and is by the no is a in and and are by this and were by with Supplementary

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