Analysis of the mechanism of renal injury at molecular levels by application of monoclonal antibodies

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Both proteinuria-inducing monoclonal antibodies (mAb) 1-22-3 and 5-1-6 are very valuable tools for analyzing the mechanism of renal injury at the molecular or epitope levels. These mAbs could induce renal lesions with extraordinary small amounts, much smaller than the previously reported minimum dose in the various experimental glomerulonephritides. Such a small amount of mAb to induce proteinuria, suggests that the recognized antigen must be limited to a critical site important in regulating the permeability of the glomerular capillary wall.In order to purify the corresponding antigen, isolated glomeruli have been labeled with 125-I by Bolton-Hunter method. Combined with gene cloning characterization of the corresponding antigen is now in progress.Not Fab but F(ab)2 as well as whole molecule of 5-1-6 could induce proteinuria. Cross-linking of the antigenic molecules on the glomerular epithelial cell surface followed by endocytosis seems to be the process, which is necessary for induction of proteinuria. Such a kinetics was investigated in vitro using isolated glomeruli by applying the various chemical agents, such as NaN3, Cyto- chalasin B or Ca-ionophore. Thus this process was demonstrated to be energy- dependent. Details will be examined further also on the signal transduction system leading to proteinuria.We have succeeded in inducing irreversible mesangial sclerotic changes with persistent proteinuria by a second injection of mAb 1-22-3 at two weeks after the first injection. It is a very valuable model for investigating the mechanism of chronic progression of human mesangial proliferative glomerulonephritis.