PATHOGENIC ANTIBODIES INHIBIT THE BINDING OF APOLIPOPROTEINS TO MEGALIN GP330 IN PASSIVE HEYMANN NEPHRITIS/

Megalin/gp330 is an endocytic receptor that internalizes multiple liga nds including apolipoproteins E (ape E) and B100 (ape B). Megalin is t he main antigenic target in passive Heymann nephritis (pHN), where it binds circulating autoantibodies leading to the formation of subepithe lial immune deposits (ID)-the hallmark of pHN. Apo E and apo B were fo und recently to accumulate within these IDs, and evidence was provided that their lipids may undergo peroxidation, causing glomerular baseme nt membrane damage and proteinuria. Here we investigated if ID-forming antimegalin IgG can inhibit the binding and internalization of apo E- beta VLDL (very low density lipoprotein) by megalin, and lead to their accumulation within IDs. By immunoelectron microscopy, apo E and apo B were detected in clathrin-coated pits and multivesicular bodies of p odocytes in control rats, suggesting that the uptake of lipoproteins i s a constitutive function of the glomerular epithelium. When pHN was i nduced by intravenous injection of antimegalin IgG, apo E and apo B we re found within IDs by inmunofluorescence and immunoelectron microscop y. Bound antibodies eluted from glomeruli of rats with pHN were found to inhibit the binding and internalization of apo E-enriched beta VLDL by megalin. These results indicate that pHN-inducing antimegalin IgG is capable of interfering with the uptake of lipoproteins by megalin i n vivo during the formation of IDs.