The permeability of glomerular basement membrane (GBM) was assessed in vitro by the filtration of solutions of proteins across films formed from isolated pig GBM. Incubation of the films with fructose or glucose increased their permeability to water and serum albumin. The effect of fructose was similar to that previously noted for films crosslinked with glutaraldehyde. The metal chelator DTPA abolished the effects of glycation; EDTA was partially effective in this respect. Transition metal catalysed formation of glycoxidation induced crosslinks may explain the increased permeability of glycated GBM.

Earlier studies indicated that chemically crosslinking glomerular basement membrane (GBM) rendered it more permeable to water and to macromolecules. Here possible mechanisms for the introduction of crosslinks into GBM under pathological conditions were explored. Glycation with glucose and with fructose over periods of 2 wk (fructose) and 6 weeks (glucose) rendered the GBM more permeable to water and myoglobin as judged from in vitro ultrafiltration behaviour. The membranes were also made more permeable to serum following glycation. The permeation changes were shown to be dependent on glycoxidative reactions judging by their inhibition by EDTA and DTPA. Aminoguanidine also prevented glycation from altering the permeability of GBM. Fluorescence studies indicated the formation of bityrosine in glycated GBM. Studies with oxidants showed that while hydrogen peroxide superoxide and peroxynitrite had little effect on GBM, hypochlorite anion was capable of increasing GBM permeability to water, myoglobin, albumin and serum. Changes in permeation were induced by very low quantities of hypochlorite, well within the range of the amounts of hypochlorite formed by activated neutrophils. Thus glycoxidation, or oxidation by hypochlorite, are chemical mechanisms by which GBM permeability can be increased.

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