Altered Functional Properties of the Renal Glomerulus in Autologous Immune Complex Nephritis

Abstract

The present study was undertaken in order to investigate the nature of the glomerular damage in a form of experimental immune complex nephritis. The model of autologous immune complex nephritis (AIC) 1 (Heymann's nephritis) (1) was chosen for several reasons. First, the model bears a remarkable resemblance, in terms of ultrastructural and immunofluorescence features, to an important renal disease in man, membranous glomerulonephritis. Furthermore, the model is highly reproducible. In addition, the basic pathogenetic mechanism has been thoroughly documented (2-4). Briefly, the disease is produced in rats by immunization with homologous kidney preparations, which results in the formation of autoantibodies against a renal antigen, normally found in the brush border of proximal tubules. This antigen is presumed to enter the circulation in small amounts and combine with autoantibody to form complexes which deposit in glomeruli. 2 The complexes are detected as granular deposits of immunoglobulin and complement along the epithelial side of the glomerular basement membrane. The disease, like its human counterpart, is manifested by proteinuria, which is often heavy.Our approach was to use the enzymatic tracers horseradish peroxidase (HRP) (40,000 daltons) and catalase (240,000 daltons), and the electronopaque tracer ferritin (ca. 500,000 daltons) as probe molecules with which to assess the altered functional properties of the glomerular capillary wall. These ultrastructural tracers can be directly visualized, and their location within the glomerular capillary wall can be followed at sequential intervals after intravenous injection. Such protein tracers have been extensively used to identify * This study was supported by U.S. Public Health Service grants no. AM 16392 and AM 13132.1Abbreviations used in this paper: AIC, autologous immune complex; CFA, complete Freund's adjuvant; CL, capillary lumen; DAB, 3,3' diaminobenzidine-tetra-HC1; GBM, glomerniar basement membrane; HRP, horseradish peroxidase; US, urinary space.It is of interest that a related pathogenetic mechanism may operate in man. It has recently been reported that a tubular-derived antigen may be present in the glomerular immune deposits in some cases of human membranous glomerulonephritis (5).

Presence of HBe Antibody in Glomerular Deposits in Membranous Glomerulonephritis Is Associated with Hepatitis B Virus Infection

“…Schneeberger et ai. [12] obtained evidence to support this view in animal experiments on autologous immune complex nephritis (Hyemann's nephritis). They used the enzymatic tracers horseradish peroxidase, cata lase, and ferritin.…”

A new role for complement in experimental membranous nephropathy in rats.

“…Similarly, based on these findings, as well as our previous studies using vasoactive amine blockers in PHN (18,22), it is apparent that immune deposit formation (and consequent proteinuria) is not dependent upon anaphylatoxin (C3a and C5a) or complement-induced vasoactive amine release from mast cells as has been demonstrated in other models (43)(44)(45). There is some evidence from tracer studies in Heymann nephritis that electrondense deposits located in the subepithelial space in the region of the slit diaphragm represent areas of increased permeability to macromolecules (46). It is therefore conceivable that alterations in the solubility of immune precipitates during incorporation of complement, as has been described in vitro (47), might give rise to areas of increased permeability resulting in loss of glomerular capillary barrier function.…”

Experimental glomerulonephritis in the isolated perfused rat kidney.

“…GBM penetration by IgG under conditions of normal flow may resemble that of ferritin if antibody is present in subgroups with sufficiently cationic isoelectric points (52). The selective concentration of the anionic ultrastructural tracer molecules, catalase and ferritin, with isoelectric points of 5.7 and 4.6, respectively, in subepithelial deposits in AICN suggests that these deposits are cationic relative to normal GBM (57). Thus, in situ formation of complexes in a discontinuous pattern on the subepithelial surface of the GBM is consistent with known mechanisms of glomerular transport and distribution of macromolecules.…”