The molecular pathogenesis of human
membranous nephropathy (MN) is unknown, despite the relatively high incidence and severity of this glomerular
immune disease.
Heymann nephritis (HN) in rats is considered an instructive experimental model of MN. This study summarizes current molecular aspects of two key events common to both MN and HN, i.e., formation of characteristic subepithelial immune deposits in the glomerular basement membrane (GBM), and development of glomerular capillary wall damage resulting in
proteinuria. In HN, the antigenic targets of immune deposit-forming
antibodies were identified in cell membranes of glomerular epithelial cells as a 515-kd
glycoprotein (
megalin, or gp330), which is a polyspecific receptor related to the
low-density lipoprotein receptor family, and an associated 44-kd
protein (receptor associated
protein, RAP). One
epitope was recently narrowed to 14
amino acids in RAP, and several others on
megalin/gp330 are under investigation.
Proteinuria requires formation of the
complement C5b-9 membrane attack complex, which is presumably triggered by
antibodies directed against
lipid antigens that associate with immune deposit-forming
megalin/gp330
immune complexes. Sublytic
C5b-9 attack on glomerular epithelial cells causes upregulation of expression of the
NADPH oxidoreductase enzyme complex by glomerular cells, which is translocated to their cell surfaces, similar to activated neutrophil granulocytes in the respiratory burst reaction. Subsequently,
reactive oxygen species (ROS) are produced locally, which reach the GBM matrix. Here formation of lipid peroxidation (LPO) adducts is found, preferentially on monomeric and dimerized NCl domains of covalently crosslinked
Type IV collagen. These structural changes within the GBM could be of functional relevance because treatment with the potent LPO-antagonist
probucol reduces
proteinuria by < 80%. Intact or fragmented
apoprotein E-containing
lipoproteins were identified as potential sources of the polyunsaturated
lipids required for the production of LPO adducts.
Lipoproteins accumulate within immune deposits and show signs of oxidative damage, similar to
oxidized LDL within atherosclerotic lesions. Collectively, the results obtained so far in HN permit the compilation of a sequence of events, linking formation of immune deposits with
proteinuria. However, despite this relatively detailed knowledge of pathogenic events in HN, the bridge to human NM remains to be built.