The previously mentioned data confirm that the novel beta-D-endoglycosidase heparanase is up-regulated and activated in glomeruli from rats with proteinuria. Heparanase may be involved, therefore, in the loss of glomerular charge seen in proteinuria. Moreover, the presence of heparanase in normal tubules suggests that it may also be involved in cell migration or turnover.

Australian New Zealand Clinical Trials Registry: ACTRN12612000023853.

SummaryA recombinant soluble form of human FcTRII (rsFcTRII) was genetically engineered by the insertion of a termination codon 5' of sequences encoding the transmembrane domain of a human FcTRII eDNA. Chinese hamster ovary cells were transfected with the modified cDNA and the secreted rsFcTRII purified from the tissue culture supernatant (to >95%, assessed by SDS-PAGE) using heat aggregated human immunoglobulin G (IgG) immunoaffinity chromatography. The IgG-purified rsFcTRII was relatively homogeneous (•31,000 Me) whereas the total unpurified rsFcTRII secreted into the tissue culture supernatant was heterogeneous relating to N-linked glycosylation differences. Functional in vitro activity of the rsFcTRII was demonstrated by: (a) ability to bind via the Fc portion of human IgG and mouse IgG (IgG2a>IgGl>>IgG2b); (b) complete inhibition of binding of erythrocytes sensitized with rabbit IgG to membrane-bound FcTRII on K562 cells; and (c) inhibition of the anti-Leu4-induced T cell proliferation assay. Blood dearance and biodistribution studies show the rsFcTRII was excreted predominantly through the kidney in a biphasic manner, with an or-phase (tl/2 '~25 min) and a r-phase (tl/2 '~4.6 h); the kidneys were the only organs noted with tissue-specific accumulation. In vivo, the administration of rsFc~RII significantly inhibited the immune complex-mediated inflammatory response induced by the reversed passive Arthus reaction model in rats. There was a specific and dose-dependent relationship between the amount of rsFcTRII administered, and the reduction in the size and severity of the macroscopic inflammatory lesion. Histological analysis of the skin showed a diffuse neutrophil infiltrate in both control and rsFcTRII-treated rats, however the perivascular infiltrate and the red cell extravasation was less intense in the rsFc~RII-treated group. It is likely that complement activation leads to neutrophil chemotaxis, but neutrophil activation via FcyRII, which results in inflammatory mediator release, is inhibited. The data indicate that rsFcyRII is a potential therapeutic agent for the treatment of antibody or immune complex-mediated tissue damage.

Drusen are common in forms of C3 glomerulopathy caused by compound heterozygous or heterozygous CFH mutations. They are useful diagnostically but also impair vision. Drusen have an identical composition to glomerular deposits. They are also identical to the drusen of age-related macular degeneration, and may respond to the same treatments. Individuals with a C3 glomerulopathy should be assessed ophthalmologically at diagnosis, and monitored regularly for vision-threatening complications.