In situ localization of type III and type IV collagen-expressing cells in human diabetic nephropathy

Nodular intercapillary glomerulosclerosis is the most typical lesion of diabetic nephropathy (DN) and is characterized by increased extracellular matrix (ECM) and amorphous masses of mesangial matrix. The local exaggeration of these deposits results in the formation in the typical diabetic nodule. To clarify the composition of the ECM of sclerotic lesions in DN, we investigated the distribution of type III and type IV collagens and their mRNAs by immunohistochemistry and in situ hybridization, respectively. In normal renal tissues, there was no intraglomerular immunostaining for type III collagen, while strongly positive staining was found in the extraglomerular interstitum. Positive immunostaining for type IV collagen was also present in the mesangium, glomerular basement membrane (GBM), Bowman's capsule, and the vascular pole of the normal glomerulus. In DN, the nodular lesions were negative for type III collagen and strongly positive for type IV collagen. On the other hand, in the late stage of global sclerosis, both type III and type IV collagens were diffusely present in the sclerotic matrix. To determine the origins of these type III and type IV collagens in the sclerotic matrix, in situ hybridization was performed, utilizing thymine-thymine (T-T) dimerized synthetic oligonucleotides complementary to either proα(III) chain or pro α1 (IV) chain mRNAs as probes. The signals were detected by enzyme immunohistochemistry using an anti-T-T antibody. Intraglomerular cells (glomerular epithelial and mesangil cells) containing type III collagen mRNA were found in DN with sclerotic lesions, but not in normal glomeruli. At this stage of sclerosis, intraglomerular cells (mainly glomerular epithelial cells and infrequently mesangial cells) were positive for type IV collagen mRNA, but there were few positive cells in globally sclerotic glomeruli. This study provides evidence that both type III and type IV collagens are synthesized by intraglomerular cells during sclerosis and become significant constituents of the sclerotic matrix in DN.     

Expression profile of extracellular matrix and its regulatory proteins during the process of interstitial fibrosis after anti-glomerular basement membrane antibody-induced glomerular sclerosis in Sprague-Dawley rats

Anti-glomerular basement membrane (GBM) nephritis in Sprague-Dawley (SD) rats was characterized by development of marked glomerular sclerosis and tubulointerstitial fibrosis. To elucidate sequential change of the glomerular sclerosis and tubulointerstitial fibrosis, accumulation and mRNA expression of extracellular matrix (ECM) components and transforming growth factor (TGF)-beta were examined in the glomerulus and cortex during the disease course by histology, immunostaining and ribonuclease protection assay. Mild proliferative and degenerative lesions appeared in the glomeruli by day 15 after anti-GBM antibody binding to GBM and progressed to glomerular sclerotic lesion thereafter. Conversely, interstitial change was first recognized by infiltration of mononuclear cells after day 20, followed by marked accumulation of ECM and tubular degeneration. The interstitial fibrosis was induced without apparent binding of anti-GBM antibody to tubular basement membrane. Accumulation of fibronectin, collagen type I and type IV was noted in the interstitium by immunofluorescence microscopy in association with enhanced expression of mRNA for these ECM components and their regulatory molecules such as matrix metalloproteinase (MMP2), tissue inhibitor of metalloproteinase (TIMP)-1 and TGF-beta1 both in glomeruli and cortex. The glomerular expression of these mRNA increased apparently by day 15 and reached a plateau or a peak at day 20. The expression of the same mRNA increased gradually from day 15 to day 29 in the cortex. These observations show that interstitial fibrosis follows glomerular sclerosis after anti-GBM antibody injection in SD rats, suggesting that at least a part of the mechanism for ECM accumulation in the glomerulus and interstitium is essentially the same in terms of composition of ECM and expression of its regulatory molecules.     

Mesangial deposition of type I collagen in human glomerulosclerosis

The presence of type I collagen in both diffuse and nodular diabetic glomerular lesions has been examined using immunohistochemical and electron microscopic techniques. At the ultrastructural level, banded collagen fibrils were observed in the mesangium in all cases of nodular (Kimmelstiel-Wilson) sclerosis and in 60% of the diffuse sclerotic lesions. Antibodies against type I collagen were localized in the fibrotic interstitium and the mesangium in all cases examined. Staining with type I collagen antibodies occurred in glomeruli with intact Bowman's capsules, and was predominantly localized to areas immediately adjacent to mesangial cells. In cases of focal sclerosis of nondiabetic origin, banded collagen fibrils and staining with anti-type I collagen antibody were observed in all cases in which the segmental lesion was presented in the specimen. The pattern of antibody localization in both the diabetic lesions and focal sclerosis differed from that obtained using anti-type IV (basement membrane) collagen antibodies. These results demonstrate that type I collagen is among the extracellular matrix components that comprise the sclerotic glomerular lesions of both diabetic and nondiabetic origin. Furthermore, the spatial localization of this collagen type suggests mesangial cell origin.     

Deficient degradation of homotrimeric type I collagen, α1(I)3 glomerulopathy in oim mice

Col1a2-deficient (oim) mice synthesize homotrimeric type I collagen due to nonfunctional proα2(I) collagen chains. Our previous studies revealed a postnatal, progressive type I collagen glomerulopathy in this mouse model, but the mechanism of the sclerotic collagen accumulation within the renal mesangium remains unclear. The recent demonstration of the resistance of homotrimeric type I collagen to cleavage by matrix metalloproteinases (MMPs), led us to investigate the role of MMP-resistance in the glomerulosclerosis of Col1a2-deficient mice. We measured the pre- and post-translational expression of type I collagen and MMPs in glomeruli from heterozygous and homozygous animals. Both the heterotrimeric and homotrimeric isotypes of type I collagen were equally present in whole kidneys of heterozygous mice by immunohistochemistry and biochemical analysis, but the sclerotic glomerular collagen was at least 95–98% homotrimeric, suggesting homotrimeric type I collagen is the pathogenic isotype of type I collagen in glomerular disease. Although steady-state MMP and Col1a1 mRNA levels increased with the disease progression, we found these changes to be a secondary response to the deficient clearance of MMP-resistant homotrimers. Increased renal MMP expression was not sufficient to prevent homotrimeric type I collagen accumulation.     

低分子量肝素降低肾衰模型大鼠IV型胶原蛋白的表达

探讨在肾小球硬化过程中 ,低分子量肝素治疗对细胞外基质和凝血酶受体表达的影响 ,用 5 6肾切除的方法诱导大鼠局灶节段性肾小球硬化模型并给予低分子量肝素治疗 2 0周 ,通过RT PCR和免疫组化法观察低分子量肝素对 5 6肾切除大鼠残肾组织中IV型胶原、凝血酶受体基因表达的影响。低分子量肝素治疗能显著降低 5 6肾切除大鼠蛋白尿、血肌酐、血脂和减轻肾组织的病理改变程度 ,并且显著下调IV型胶原、凝血酶受体mRNA表达。结果提示低分子量肝素可能通过影响凝血酶受体mRNA表达 ,减轻肾小球重塑过程中细胞外基质的异常代谢、沉积。     

Mesangial sclerotic change with persistent proteinuria in rats after two consecutive injections of monoclonal antibody 1-22-3.

Irreversible mesangial changes with persistent proteinuria were induced in rats given two consecutive injections 2 weeks apart of a MoAb 1-22-3 to rat mesangial cell. The characteristics of the resulting lesions were investigated and compared with those of the reversible change induced by a single injection. At 24 h after the second injection, mesangiolytic changes similar to those after a single injection were evident. The accumulation of macrophage-like cells in glomeruli observed at 1 week after the first injection was not evident during the experimental period after the second injection. Hypercellularity with the characteristics of intrinsic mesangial cell and increased mesangial matrix were already present 1 week after the second injection. And mesangial sclerotic change progressed up to 6 months. Deposition of collagen type I and type III and accumulation of collagen fibril at the ultrastructural level were evident in rats 6 months after the second injection. Proteinuria started immediately and continued for more than 6 months after the second injection. The mesangial sclerotic change with persistent proteinuria described here is considered to be a better model for investigating the mechanism of chronic progression of human mesangial proliferative glomerulonephritis.     

Studies of progressive glomerular sclerosis in the rat.

To obtain a better understanding of the sequential development of sclerosis in immune glomerular disease, the authors induced experimental membranous nephropathy in unilaterally nephrectomized rats and evaluated the lesions that developed over a 35-week period. Serial renal biopsies were examined by light and immunofluorescence microscopy for IgG, C3, neoantigens of the membrane attack complex (MAC), and interstitial (Type III) and basement membrane (Type IV) collagen. Urinary protein excretion increased from 208 +/- 19 mg/day to 308 +/- 36 mg/day during the period of observation. Progressive mesangial sclerosis, crescent formation, and interstitial fibrosis developed in association with deposition of Type IV but not Type III collagen in the glomeruli. Capillary wall deposits of IgG, C3, and MAC gradually decreased, whereas coarse granular deposits of C3 and MAC were visible in sclerotic areas beginning at 8 weeks. The appearance of complement components in early sclerotic lesions raises the possibility that they are of pathogenetic importance. The absence of interstitial collagen in sclerotic glomeruli suggests that the components of the lesion are produced solely by glomerular cells.     

Uninephrectomy induces progressive glomerulosclerosis and apoptosis in anti-Thy1 glomerulonephritis

Administration of the anti-Thy1 antibody in rats induces reversible glomerulonephritis resembling human mesangiolytic and mesangioproliferative diseases. The purpose of the present study was to design a model of irreversible glomerulosclerosis, using the anti-Thy1 antibody injection after uninephrectomy, and examine it, focusing on apoptosis in the process of progressive sclerotic changes. Wistar rats were divided into three groups: one-kidney groups (group I and III) and a two-kidney group (group II). All groups were injected with the anti-Thy1 antibody (OX-7) at day 0, and group I and III were uninephrectomized at day -6. Only group III rats were given a half dose of OX-7 as compared with group I and II. Rats were killed for histological examinations at days 7, 14 and 30. In group I, progressive glomerular lesions, such as glomerular adhesion to Bowman's capsule, crescent formation, and collapse of capillary tufts were observed at days 14 and 30. No significant differences were observed in the pathological findings between group I and III. There was a significantly higher number of glomerular terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells in group I as compared to group II at days 7 and 14. Moreover, the glomerular expression of transforming growth factor-beta, heparan sulfate proteoglycan and chondroitin sulfate proteoglycan significantly increased in group I as compared to group II at days 7 and 14. Progressive glomerulosclerosis can be induced in the rat by a single injection of the anti-Thy1 antibody after unilateral nephrectomy. It is suggested that apoptosis and extracellular matrix accumulation play an important role in the development of glomerulosclerosis.     

Alteration of glomerular permeability to macromolecules induced by cross-linking of beta 1 integrin receptors.

Altered glomerular epithelial cell attachment to the glomerular basement membrane is an important pathogenetic factor in increased glomerular permeability to proteins. We have previously presented evidence that antibodies reactive with integrin matrix receptors on glomerular epithelial cells inhibit adhesion of these cells and may be involved in the production of proteinuria in vivo. Therefore, we utilized intact glomeruli in an in vitro system to directly assess the effect of anti-beta 1-integrin antibody on glomerular permeability. Permeability to albumin (Palb) was calculated from the volume response of glomeruli to a transcapillary oncotic gradient. Anti-beta 1-integrin increased Palb in a dose- and time-dependent manner. Palb was increased to 0.70 +/- 0.05 whereas normal rabbit IgG had no effect (0.10 +/- 0.04). F(ab')2 fragments of antibody increased Palb to a similar degree whereas Fab fragments had no effect (0.10 +/- 0.06). Cross-linking of Fab fragments, however, with a second antibody restored their ability to increase Palb (0.60 +/- 0.09), demonstrating the importance of integrin cross-linking in producing the observed effect. Intact, F(ab')2 and Fab fragments of anti-beta 1 antibody all inhibited adhesion of glomerular epithelial cells to fibronectin, laminin, and types I and IV collagen, although the degree of inhibition by Fab fragments was significantly less on collagens. No cytotoxic effects were observed with anti-beta 1 antibody or its fragments. These results suggest that antibodies to integrin matrix receptors on glomerular cells alter cell interactions with the glomerular basement membrane and lead to increased glomerular permeability to proteins via a process that is initiated by integrin cross-linking rather than through simple interference with cell adhesion per se.     

Transient expression of type I collagen in glomeruli with anti-Thy-1 antibody-induced mesangial proliferative lesions

Glomerular expression of extracellular matrices at the protein and mRNA levels was examined in rats with mesangial proliferative glomerulonephritis induced by the intravenous administration of a monoclonal anti-rat Thy-1 antibody. In close association with the mesangial proliferative lesion, type I collagen was imrnunostained at day 8 but not demonstrated at day 28 in the glomeruli of the kidneys. Type I collagen mRNA expression prominently increased in the nephritic glomeruli at day 4, prior to the appearance of type I collagen protein. In addition, fibronectin expression was also elevated in the diseased glomeruli at both the protein and mRNA levels. These results indicated that glomerular, probably mesangial cells, change their phenotypes during this disease, to synthesize abnormal extracellular matrices that lead to the progression of glomerular sclerosis.     

A histologic study of the extracellular matrix during the development of glomerulosclerosis in murine chronic graft-versus-host disease.

The development of glomerulosclerosis was studied in murine chronic graft-versus-host disease (GvHD), which is a model for human systemic lupus erythematosus. The authors investigated the distribution patterns of six components of the extracellular matrix (ECM), i.e., laminin, fibronectin, collagen types I, III, IV, and VI during the course of the disease. All of these ECM components except collagen type I were found in the glomeruli of normal mice, where all of them were intrinsic constituents of the mesangium. Laminin, fibronectin, and collagen type IV were also found in the glomerular capillary walls. Starting 6 weeks after the induction of GvHD and continuing at week 8, the onset of an expansion of the mesangial matrix was observed. At the same time, the amounts of laminin, fibronectin, and collagen types IV and VI increased. Ten weeks after the onset of the disease, glomerulosclerosis developed. Traces of the interstitial collagen type I were found in sclerotic glomeruli. The levels of four ECM components, i.e., collagens III, IV, VI, and laminin were markedly decreased in the sclerotic glomeruli as compared with week 8. In contrast, the amount of fibronectin in the sclerotic glomeruli increased dramatically. Immunoelectron microscopic examination showed fibronectin in the sclerotic lesions, in contrast to laminin, collagen type I, and collagen type IV. It is concluded that the sclerotic lesions in murine chronic GvHD contain fibronectin. The small amounts of the ECM components laminin, as well as collagens III, IV, and VI in the sclerotic glomeruli in GvHD, might represent remnants of mesangial material and collapsed capillary walls. These components are probably replaced by increased production and/or accumulation of collagen type I and fibronectin.     

Transforming growth factor-beta receptors in self-limited vs. chronic progressive nephritis in rats

Increases in transforming growth factor-beta (TGF-beta) expression and extracellular matrix accumulation are transient in acute self-limited mesangial proliferative glomerulonephritis induced by a single injection of anti-thymocyte serum (ATS), while these increases persist following repeated injections that produce chronic progressive sclerosing glomerulonephritis with tubulointerstitial lesions. However, little is known about the expression of TGF-beta receptors (TbetaRs) in cells involved in the proliferative and sclerosing renal lesions. A study of protein and mRNA expression for type I (TbetaRI), type II (TbetaRII), and type III (TbetaRIII) TbetaR in both forms of nephritis was therefore carried out by immunohistochemistry and in situ hybridization. Inhibition of cell proliferation and stimulation of matrix production by TGF-beta1 were assessed in isolated glomeruli using [(3)H]thymidine incorporation and [(3)H]proline metabolic labelling, respectively. In acute self-limited nephritis, expression of TbetaRI, TbetaRII, and TbetaRIII increased in the glomerular and Bowman's capsular epithelial cells comprising the glomerular tuft adhesions to Bowman's capsules. However, TbetaRII expression was not prominent in proliferating mesangial cells. Glomeruli isolated from rats with acute self-limited nephritis at day 7, when mesangial cell proliferation was maximal, were partially resistant to the mitoinhibitory effects of TGF-beta1. In contrast, expression of all three TbetaRs was elevated in glomerular and tubulointerstitial lesions in chronic progressive nephritis, and glomeruli isolated from rats with chronic progressive nephritis 7 days after the second ATS injection were sensitive to TGF-beta1. These data suggest that distinct cellular responses to TGF-beta1 resulting from differential expression of TbetaR underlie the difference between acute self-limited mesangial proliferative and chronic progressive sclerosing ATS nephritis in the development of proliferative and sclerotic renal lesions.     

Different types of segmental sclerosing glomerular lesions in six experimental models of proteinuria

From 133 to 615 glomeruli were examined in sections of kidneys from each of 60 animals, representing six rodent models of proteinuria. Particular attention was paid to the position of segmental lesions. Lewis rats given sheep anti-rat glomerular basement membrane antibodies had lesions almost exclusively at the glomerulo-tubular junction. Wistar rats on a diet of 24 per cent casein or with subtotal nephrectomy and a diet of 24 per cent soya had lesions mainly at the hilum. Wistar rats given bovine serum albumin had global lesions but virtually no segmental lesions. Wistar rats given puromycin aminonucleoside had lesions at the glomerulo-tubular junction and global mesangial abnormalities shortly after the treatment but later developed segmental lesions at all parts of the glomerulus. Untreated BUF/Mna rats had lesions at the glomerulo-tubular junction early in life but later had lesions at all parts of the glomerulus. Untreated NZB/NZW hybrid mice had various types of glomerulonephritis and also had lesions at the glomerulo-tubular junction. These findings showed that (1) segmental lesions at the glomerulo-tubular junction, or glomerular tip, occur in experimental animals, a fact not previously reported, and these tip changes are a common feature in several different models of proteinuria; (2) hilar segmental lesions are seen in conditions with hyperfiltration of protein; and (3) segmental lesions at various parts of the glomerulus are seen in some models of proteinuria and probably indicate late effects of random toxic damage to the glomerulus. Thus, there are at least three different types of segmental glomerular lesions in experimental animals--tip, hilar, and random--with different morphology and pathogenesis. It is likely that these findings can be extended to human renal diseases with segmental glomerular lesions. This will help to clarify the controversial and unsatisfactory term focal segmental glomerulosclerosis.     

Alterations in extracellular matrix components and integrins in patients with preeclamptic nephropathy

The glomerular features of patients with preeclapsia consist of swelling of endothelial cells, subendothelial deposits of incompletely defined material, and thickening of the capillary walls. These abnormalities are thought to resolve in the postpartum period. The distribution of extracellular matrix (ECM) components and integrins was investigated in 10 such patients. Frozen sections and paraffin-embedded sections were stained with antibodies to type IV collagen, laminin (LN), fibronectin (FN), vitronectin (VN), tenascin (TN), fibronectin receptor (FNR), and vitronectin receptor (VNR). In preeclamptic nephropathy, the accumulation of type IV collagen, LN, FN, TN, and FNR was observed in the thickened capillary walls, particularly in the subendothelial layer and, to some extent, in the mesangium. However, deposits of VN were sparse and the distribution of VNR was similar to that in normal kidney. In segmental sclerotic lesions, the amounts of type IV collagen, LN, FN, VN, and TN were increased, whereas those of FNR and VNR were markedly decreased. These results suggest that the materials deposited in the subendothelial space consist of ECM components as well as of plasma-derived proteins, and that the deposition of ECM components and of FNR may be involved in the development and the reparative process of the characteristic glomerular lesions. The formation of sclerotic lesions was linked to the accumulation of ECM components, but not to an interaction with integrins.     

Rare glomerular capillary regeneration and subsequent capillary regression with endothelial cell apoptosis in progressive glomerulonephritis.

Glomerulonephritis (GN) leading to glomerular sclerosis remains an important cause of renal failure. The glomerulus is a capillary network, but endothelial and vascular reactions during progressive GN are not well understood. We have, therefore, examined the morphological alterations of glomerular capillary network and endothelial cells during the progression of damaged glomeruli to glomerular sclerosis. A progressive model of anti-glomerular basement membrane (GBM) GN was induced in Wistar-Kyoto (WKY) rats with a single injection of anti-rat GBM antibody. Severe necrotizing glomerular injuries were observed between day 5 and week 3 with a reduction in the number of total glomerular endothelial cells and total glomerular capillary lumina per glomerular cross sections. In necrotizing lesions, the glomerular endothelial cells were lost with the destruction of the glomerular capillary network. Moreover, angiogenic capillary repair with proliferation of endothelial cells was rare in severely damaged regions of glomeruli. Subsequently, mesangial hypercellularity and marked mesangial matrix accumulation occurred with absence of the development of a capillary network, and the necrotizing lesions progressed to sclerotic scars until 8 weeks. Although active necrotizing lesions could not be seen in damaged glomeruli between week 4 and week 8, the number of apoptotic endothelial cells gradually increased in the glomerular capillaries (0.10 +/- 0.01 apoptotic endothelial cells/glomerular cross section at week 8 versus 0.00 +/- 0.00 control cells (mean +/- SEM; P < 0.05) with the progression of glomerular sclerosis. Whereas the number of apoptotic endothelial cells increased in the damaged glomeruli, the number of total glomerular endothelial cells decreased (9.3 +/- 3.0 cells/glomerular cross section at week 8 versus 24.8 +/- 3.0 cells in control (mean +/- SD); P < 0.001) with regression of glomerular capillaries (3.6 +/- 2.5 capillary lumina/glomerular cross section at week 8 versus 35.0 +/- 5.0 capillary lumina in control (mean +/- SD); P < 0.001). Finally, glomerular endothelial cells could not be detected in the sclerotic lesions in progressive anti-GBM GN in WKY rats. These data indicate that the destruction of the capillary network of glomeruli and subsequent incomplete angiogenic capillary repair leads to glomerular sclerosis in progressive GN. Endothelial cell apoptosis with glomerular capillary regression may also contribute to the development of glomerular sclerosis. Injury of the glomerular capillary network with endothelial cell damage, including apoptosis and subsequent incomplete capillary repair, plays an important role in the progression of glomerular sclerosis during anti-GBM GN in WKY rats.     

RETARDED MESANGIAL TRANSPORT AND ITS PATHOMORPHOLOGIC SEQUELAE IN HUMAN AND EXPERIMENTAL RENAL DISEASES

Human renal biopsy specimens (472 cases) from varied kidney diseases, especially minimal glomerular change group and other idiopathic glomerular diseases having nephrotic manifestation of mainly juvenile individuals, showed morphologic evidence of paraarterial deposits of afferent arterioles at the glomerular entrances in more than 50% of examined cases. Because these deposits were often accompanied with concomitant mesangial, intraarterial and subendothelial deposits of afferent arterioles, it was felt that retarded mesangial transport which is ordinarily associated with certain glomerular diseases might be an important factor to produce these particular paraarterial deposits. The referred deposits of minimal glomerular change group cases were thought to predispose the occurrence of focal sclerotic capillary lesions at the vascular poles of glomeruli. The experimental chronic nephrotic rats produced by daily administration of aminonucleoside of puromycin revealed mesangial dysfunction with increased uptake and retarded disposal of secondarily overloaded aggregated human gamma globulin at mesangial areas in glomeruli. Besides, the increased deposits of autologous serum proteins in mesangial areas and arteriolar walls were common findings in those rats, and these deposits were observed to be always preceded to the occurrence of segmental sclerotic changes of glomeruli, which were often associated in the later stage of this experiment. ACTA PATHOL. JPN. 33: 219∼236, 1983.     

Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats

Anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats is characterized by glomerular accumulation of CD8(+) T cells and monocytes/macrophages, followed by crescent formation. The mechanism of leukocyte accumulation after antibody binding to GBM is still unclear. To unveil an involvement of Fcgamma receptors (FcgammaR) in leukocytes recruitment we examined the expression of FcgammaR in glomeruli and the effects of the administration of F(ab')(2) fragment of anti-GBM antibody or FcgammaR blocking on the initiation and progression of this model. A gradual increase of FcgammaR mRNA expression in glomeruli during the time course of disease suggested their significance in the development of glomerulonephritis. Glomerular lesions and proteinuria were induced only in rats injected with intact IgG of anti-GBM antibody, but not with the F(ab')(2) fragment. In vivo blocking of FcgammaR by administering heat-aggregated IgG led to the decrease of mRNA expression for all types of FcgammaR (types 1, 2 and 3) and a significant amelioration of glomerulonephritis manifestations. By flow cytometry and immunohistochemistry FcgammaR2-expressing cells in glomeruli were identified as macrophages, but not CD8(+) T cells. The expression of FcgammaR1 and 3 was significantly decreased, and that of FcgammaR2 became undetectable in CD8(+) T cell-depleted rats. Thus, CD8(+) T cells may stimulate FcgammaR expression on macrophages, contributing to their glomerular accumulation and injury. These studies provide direct evidence for a crucial involvement of IgG Fc-FcgammaR interaction in glomerular recruitment of macrophages and following induction of anti-GBM glomerulonephritis in WKY rats.     

New rat model induced by anti-glomerular basement membrane antibody shows severe glomerular adhesion in early stage and quickly progresses to end-stage renal failure

The aim of the present study was to introduce a new anti-glomerular basement membrane nephritis model in which plasma creatinine levels dramatically increased only 4 weeks after a single administration of rabbit antirat glomerular basement membrane antibody in Sprague–Dawley rats. According to renal morphology, glomerular lesions characterized by mesangial expansion and adhesion of the glomerular tuft to Bowman's capsule were observed in the early stage at day 7 after disease induction; adhesion was detected in approximately 90% of glomeruli 14 days after antibody injection. After 21 days the rats exhibited pronounced glomerulosclerosis/hyalinosis and severe tubulointerstitial lesions characterized by interstitial fibrosis. Urinary podocytes excreted in nephritis rats were studied and it was found that urinary podocyte loss might be closely related to progression of renal injury. Because this new model simply and reproducibly demonstrates development of end-stage renal disease, it will be beneficial for elucidating mechanisms by which chronic renal injury irreversibly progresses, as well as for developing therapeutic agents for chronic renal failure.     

A novel transcription factor is correlated with both glomerular proliferation and sclerosis in the rat renal ablation model

Glomerular accumulation of the extracellular matrix (ECM) with subsequent sclerosis is a common finding in most progressive renal diseases. Recently MSW (Mouse South Western) protein was cloned by its ability to bind the bidirectional promoter of the collagen IV genes. This protein was also reported as the large subunit of the DNA replication complex A1, as well as the promoter binding protein of corticotropin-releasing hormone and the angiotensinogen gene. To investigate the mechanism of accumulation of the ECM as it relates to glomerular cellular events, the expression of MSW protein was studied in the remnant kidney model. Progressive expression of MSW protein was found in the glomerular sclerotic lesion at week 4 and at later time points after renal ablation. The expression of proliferating cell nuclear antigen (PCNA) and type IV collagen was also correlated with the expression of MSW protein by immunofluorescence. RNA dot blot analysis also showed that the expression of MSW mRNA was increased at week 7 in association with the augmented expression of type IV collagen. These results, taken together, suggest that MSW protein plays an important role in the regulation of type IV collagen gene expression in vivo and may contribute to glomerular cell proliferation and the development of glomerulosclerosis.© 1997 by John Wiley & Sons, Ltd.