Disease relevance of Cfh

• Here we show that mice deficient in factor H (Cfh(-/-) mice) develop MPGN spontaneously and are hypersensitive to developing renal injury caused by immune complexes [1].
• C57BL/6 factor H-deficient mice (Cfh(-/-)) and wild-type (wt) controls were immunized daily for 5 wk with heterologous apoferritin to study the chronic serum sickness GN model [2].
• Relative to the WT recipients of WT kidneys, WT mice with Cfh(-/-) kidneys (n = 12) developed glomerular disease features, including increased albuminuria (82.8 +/- 7.0 versus 45.1 +/- 3.6 mug/mg creatinine; P < 0.001) and blood urea nitrogen levels (54.4 +/- 6.1 versus 44.2 +/- 3.7 mg/dl; P < 0.01) [3].
• Diffuse proliferative glomerulonephritis (GN) occurred in WT kidneys that were transplanted into Cfh(-/-) recipients (n = 8) but not into WT recipients (n = 14), consistent with the importance of plasma Cfh to dictate outcome in this disease model [3].

High impact information on Cfh

• Introducing a second mutation in the gene encoding complement factor B, which prevents C3 turnover in vivo, obviates the phenotype of Cfh(-/-) mice [1].
• Using an interspecific cross, gene linkage relationships among members of the murine complement receptor-related genes, C4bp, Cfh, Mcry, and Mcr2, were analyzed by segregation of RFLP in 200 mice [4].
• At 12 months there was a significant reduction in mortality, glomerular cellularity, neutrophil numbers, and serum creatinine levels in Cfh(-/-) mice deficient in C5 [5].
• Following the inheritance of DNA restriction fragment-length polymorphisms revealed by the probes in recombinant inbred mouse strains allowed the factor H-associated fragments to be mapped to Sas-1 on chromosome 1, and the C5-associated fragments to be mapped to Hc [6].
• These data suggest that locally produced podocyte Cfh is important to process immune complexes in the subepithelial space, where it also limits complement activation [3].

Chemical compound and disease context of Cfh

• We investigated the role of C5 activation in a model of MPGN that develops spontaneously in complement factor H-deficient mice (Cfh(-/-)) [5].

Biological context of Cfh

• Consistent with the increase in glomerular immune complexes and possibly because of alternative pathway complement activation, Cfh(-/-) mice had increased glomerular C3 deposition [2].
• Genetic linkage between Lym-1, Sas-1 and Mls loci [7].
• In order to evaluate the distribution and the pharmacokinetics of NOM, [O-methyl-3H]NOM was administered to and followed in mice [8].
• In both liver and brain, the radioactivity content decreased over time with similar kinetics reflecting the diffusion and metabolism of NOM and of its metabolites [8].

Anatomical context of Cfh

• In contrast, wild-type mice with Cfh(-/-) bone marrow had reduced platelet-associated immune complexes and extensive glomerular deposition of complement-activating immune complexes, but they did not develop glomerular pathology [9].
• Just as in platelets, rodent podocytes seem to use Cfh as the functional surrogate for human complement receptor 1 [3].
• Complement factor H (Cfh) is a key plasma protein in humans and animals that serves to limit alternative pathway complement activation in plasma, as well as in local sites such as capillaries of the glomerulus and eye [3].
• (MGD)2-Fe2+-NO was observed in the brain of NOM-treated mice in the first 10 min following injection, revealing that NOM was able to cross the blood-brain barrier, while GSNO was not [8].

Associations of Cfh with chemical compounds

• We have designated the two loci Cfh and C5, respectively [6].
• The advantage of NOM, a very lipophilic drug, is its ability to release both melatonin and NO*, an easily diffusible free radical [8].
• The behaviour of NOM was compared with that of GSNO (S-nitrosoglutathione), a hydrophilic NO* donor [8].
• The N-nitroso-derivative of melatonin, NOM (1-nitrosomelatonin), which has been demonstrated to be a NO* [oxidonitrogen*] donor in buffered solutions, is a new potential drug particularly in neurological diseases [8].
• A complementary method for monitoring NOM, EPR, was performed in vitro and ex vivo with (MGD)2-Fe2+ (iron-N-methyl-D-glucamine dithiocarbamate) complex as a spin trap [8].

Other interactions of Cfh

• Placement of the Ly5 gene with respect to other characterized markers of mouse chromosome 1 for these recombinant inbred mouse strains shows a gene order of Idh-1:Ity:Pep3:[Ly5, Cfh] [10].
• The evidence also suggests that Sas-2 is genetically different from the previously described Sas-1 which controls a serum protein in the mouse [11].
• Sas-1, B2m, and b on chromosomes 1, 2, and 4 were linked to significant (P less than .05) differences in virus-induced mortality; d on chromosome 9 was associated with a similar but smaller difference (.1 greater than P greater than .05) [12].

Analytical, diagnostic and therapeutic context of Cfh

• Immunizations were started in 6- to 8-wk-old mice, which was before the development of spontaneous membranoproliferative glomerulonephritis in some Cfh(-/-) animals [2].
• For dissection between the two, bone marrow chimeras between Cfh-deficient (Cfh(-/-)) and wild-type C57BL/6 mice were created [9].

References