Altered anionic GBM components in monoclonal antibody against slit diaphragm-injected proteinuric rats

Fujigaki, Yoshihide; Nagase, Mitsumasa; Hidaka, Sumi; Matsui, Katsuyuki; Shirai, Masaki; Nosaka, Hitonari; Kawachi, Hiroshi; Shimizu, Fujio; Hishida, Akira

doi:10.1046/j.1523-1755.1998.00131.x

Cited by 13 publications

(14 citation statements)

References 21 publications

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“…When glomerular permeability for albumin is enhanced, the distribution of albumin in the GBM would be expected to shift towards the outer (epithelial) side of the GBM. This expected alteration in the distribution of endogenous albumin could in fact be demonstrated in a previous study in proteinuric rats [14]. Therefore, we believe that it is possible to detect and interpret subtle changes of permeability in the glomerular filter by studying alterations in the localization of endogenous albumin using the present technique.…”

Section: Discussionsupporting

confidence: 75%

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Sequence of events in the glomerular capillary wall at the onset of proteinuria in passive Heymann nephritis

Fujigaki

Batsford²,

Yamashita

et al. 2001

Virchows Archiv

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Proteinuria in passive Heymann nephritis (PHN) results from complement-mediated glomerular injury, since complement depletion with cobra venom factor (CVF) prevents proteinuria. However, there are no comprehensive morphological studies identifying the sites of injury leading to onset of proteinuria. To address this issue, we attempted to locate sites of injury involved in the onset of proteinuria in PHN. PHN was induced in intact Munich-Wistar rats (PHN-rats, examined at days 3, 5, and 7) and in complement-depleted rats (CVF treated, PHN-CVF-rats, examined at days 3 and 5). The distribution of endogenous albumin in the glomerular basement membrane (GBM) was studied in in situ drip-fixed glomeruli using immunogold immunocytochemistry, and glomerular anionic sites were visualized by polyethyleneimine staining. In addition, the ultrastructural localization of an epitope recognized by a proteinuria-inducing monoclonal antibody (called 5-1-6) directed against the slit diaphragm was examined. Significant proteinuria was seen in intact PHN-rats, starting at day 5. The intensity of gold labeling for endogenous albumin was significantly increased at the outermost site of the GBM (GBM interfacing foot process and the filtration slit, designated area O) at day 3 in both PHN-rats and PHN-CVF-rats in comparison to untreated controls. At day 5, labeling for albumin in area O was decreased in PHN-rats, but not in PHN-CVF-rats, where it was then higher; in PHN-rats, some areas between epithelial cells and subepithelial deposits were almost free of albumin labeling at day 7. There was no evidence of epithelial cell detachment in any group at day 5, but on day 7 limited focal detachment was seen exclusively in PHN-rats. In proteinuric rats, amorphous material that stained for albumin could be seen in the urinary space, without any exocytosis of labeling by glomerular epithelial cells. A significant reduction of intensity of staining for anionic sites was seen in parallel in both groups, but only in the regions of the lamina rara externa adjacent to subepithelial deposits. This local loss of charge might contribute to enhanced permeability to albumin in both PHN- and PHN-CVF-rats. Changes in the appearance of the filtration slits and in the density and distribution of antigen recognised by monoclonal antibody 5-1-6 were similar in PHN- and PHN-CVF-rats at day 5. Complement depletion prevented neither the reduction in anionic sites of the GBM nor the changes in the slit diaphragm observed. These data suggest that albumin leakage between the epithelial cell and the GBM (area O) could occur in PHN-rats, perhaps as a result of epithelial foot-process changes. This may be the final link in the chain of events responsible for the onset of proteinuria in PHN.

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Section: Discussionsupporting

confidence: 75%

“…An epitope on an antigen of the slit diaphragm, which is recognized by MoAb 5-1-6, has been shown to regulate glomerular permeability in rats [13,14,26] and al- terations in the quantity and/or distribution of this antigen could be expected to be associated with proteinuria.…”

Section: Discussionmentioning

confidence: 99%

Sequence of events in the glomerular capillary wall at the onset of proteinuria in passive Heymann nephritis

Fujigaki

Batsford²,

Yamashita

et al. 2001

Virchows Archiv

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“…The GBM poses anionic sites (33) consisted of glucosaminoglycans (34) and the decrement of such sites is presumed to reflect dysfunction of the charge selective barrier in nephrotic syndrome (26,34,35). In addition, the differential clearance study by Lund et al (36) using neutral and native forms of albumin indicated that the fractional clearance of neutral albumin …”

Section: Takahashi Et Almentioning

confidence: 99%

“…Recent studies by Jeansson and Haraldsson (41) suggested the importance of endothelial glycocalyx in the charge-selective property of GCW. Unless impairment of the slit diaphragm may influence the anionic sites of GBM (35), the group A diseases are not likely to completely lose their charge-selective properties. This is supported by the cases of FCNS and FSGS since these diseases showed a worse SI with a better CSI than group A.…”

Section: Charge Barrier In Glomerular Diseasesmentioning

confidence: 99%

Charge Selective Function in Childhood Glomerular Diseases

et al. 2006

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“…We have already reported some investigations of the pathogenesis of mAb 5-1-6 nephropathy, 6,40,[58][59][60][61][62][63] and investigations of the expression of mAb 5-1-6 antigen in the proteinuric state [64][65][66][67] and in the developing glomeruli. 48,68 All our observations on the expression of mAb 5-1-6 antigen reported previously should be interpreted as observations on the expression of nephrin.…”

Section: Anti-nephrin Mab 5-1-6 Nephropathymentioning

confidence: 99%

Molecular composition and function of the slit diaphragm: nephrin, the molecule responsible for proteinuria

Kawachi

Shimizu

2000

Clinical and Experimental Nephrology

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Although the role of the glomerular basement membrane has been emphasized as the barrier for retaining plasma proteins, some recent studies have clearly shown that the slit diaphragm is the structure most likely to be the main barrier in the glomerular capillary wall. Nephrin, ZO-1, Pcadherin and FAT are reported to be components of the slit diaphragm. Of these molecules, the molecular natures of ZO-1 and nephrin are relatively well investigated. ZO-1 was originally identified as a component of the tight junction. Nephrin was identified as a gene product mutated in congenital nephrotic syndrome. ZO-1 is localized at the cytoplasmic surface just at the insertion point of the slit diaphragm, whereas nephrin is located at the outer leaflet of plasma membranes. The expression of nephrin is decreased in several kinds of proteinuric states, and anti-nephrin monoclonal antibody (mAb) 5-1-6 is capable of inducing massive proteinuria, which indicates that nephrin is a functional protein in the slit diaphragm. Nephrin is expected to be a target of therapy for proteinuria. A model of nephrin assembly that forms the structure of the slit diaphragm has been proposed. However, we observed that the slit diaphragm structure was maintained in mAb 5-1-6 nephropathy, although nephrin expression was dramatically decreased. These findings suggest that nephrin is not essential for maintaining the structural integrity of the slit diaphragm. Although it has been proposed that P-cadherin is a core protein in the slit diaphragm, this hypothesis is still controversial. To better understand the structure of the slit diaphragm, it is particularly important to identify other components that build up the structure of the slit diaphragm together with nephrin and ZO-1.

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Altered anionic GBM components in monoclonal antibody against slit diaphragm-injected proteinuric rats

Cited by 13 publications

References 21 publications

Sequence of events in the glomerular capillary wall at the onset of proteinuria in passive Heymann nephritis

Sequence of events in the glomerular capillary wall at the onset of proteinuria in passive Heymann nephritis

Charge Selective Function in Childhood Glomerular Diseases

Molecular composition and function of the slit diaphragm: nephrin, the molecule responsible for proteinuria

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