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1.  Natural Recovery from Antiglomerular Basement Membrane Glomerulonephritis Is Associated with Glomeruli-Infiltrating CD8α+CD11c+MHC Class II+ Cells 
American Journal of Nephrology  2011;34(6):519-528.
Background/Aims: In an antiglomerular basement membrane glomerulonephritis (GN) model, GN-resistant Lewis (LEW) rats naturally recover from early glomerular inflammation (days 21–23). We have previously identified a glomeruli-infiltrating CD8α+CD11highMHC II+ cell (GIL CD8α+ cell) in GN-prone Wistar Kyoto (WKY) rats, which terminates glomerular inflammation through inducing T cell apoptosis prior to glomerular fibrosis at days 35–40. We investigated if GIL CD8α+ cells were also associated with the recovery in LEW rats. Methods: GIL CD8α+ cells in LEW rats were characterized; their infiltration was observed in connection with T cell apoptosis in glomeruli. Results: An influx of GIL CD8α+ cells into inflamed glomeruli was confirmed in the immunized LEW rats at days 17–22, which was much earlier than days 28–35 in WKY rats. Notably, LEW rats had a GIL CD8α+CD11high subpopulation after day 17, while WKY rats lacked this population until after day 30. Analyses further revealed a large number of clustered apoptotic CD4+ or CD3+ T cells in the glomeruli during recovery (day 23) in LEW rats, as compared to day 35 (transition to fibrosis) in WKY rats. Thus, infiltration of GIL CD8α+ cells coincided with decline of glomerular inflammation and T cell apoptosis during recovery in LEW rats. Isolated GIL CD8α+ cells were able to infiltrate glomeruli in both WKY and LEW rats at day 20. Conclusion: Our data revealed a strong association between GIL CD8a+ cells and recovery from early glomerular inflammation. It raises a possibility of involvement of GIL CD8a+ cells in the recovery.
PMCID: PMC3237105  PMID: 22068125
Glomerulonephritis; Immunosuppression; Animal models; Apoptosis
2.  Blockade of Osteopontin Inhibits Glomerular Fibrosis in a Model of Anti-Glomerular Basement Membrane Glomerulonephritis 
American Journal of Nephrology  2010;32(4):324-331.
In our rat model for anti-GBM GN, severe fibrosis follows glomerular inflammation. A potential role of extracellular matrix protein osteopontin (OPN) in glomerular fibrosis was investigated.
Neutralizing OPN antiserum or control normal serum was injected into the experimental rats at late inflammatory/early fibrotic stage. Glomerular inflammation and fibrosis were determined.
OPN antiserum treatment had little effect on glomerular inflammation. However, the antiserum treatment resulted in a significant reduction in number of fibrotic glomeruli (50% of the controls). Histology observation showed that fibrotic tissue in glomeruli of the antiserum treated rats was mild and poorly developed. OPN antiserum treatment resulted in downregulated glomerular expression of collagen 1α1; collagen deposition in the antiserum treated rats reduced to <30% of that for normal serum controls.
Neutralization of OPN inhibited progression of fibrosis in vivo when given at early fibrotic stage. Thus, OPN may be a therapeutic target for glomerular fibrosis.
PMCID: PMC2969149  PMID: 20720406
Fibrosis; Extracellular matrix; Glomerulonephritis; Animal models
3.  Osteopontin Overproduction Is Associated with Progression of Glomerular Fibrosis in a Rat Model of Anti-Glomerular Basement Membrane Glomerulonephritis 
American Journal of Nephrology  2010;32(3):262-271.
Glomerular fibrosis is the common end result of glomerulonephritis (GN) regardless of etiology. In our rat model for anti-glomerular basement membrane GN, severe fibrosis follows glomerular inflammation. We investigated the association between expression of extracellular matrix (ECM) proteins and progression of glomerular fibrosis.
Expression of ECM genes in glomeruli was determined at RNA and protein levels. Immunofluorescence was applied to identify cell sources for the molecules.
DNA microarray for ECM genes, quantitative RT-PCR and Western blot revealed significant upregulation of osteopontin (OPN), a multifunctional molecule, in the glomeruli only after onset of glomerular fibrosis. Two-dimensional electrophoresis showed that the expressed OPN was in three major isoforms. Immunofluorescence showed that fibrotic tissues in glomeruli accumulated massive deposits of extracellular OPN. Both in vivo and in vitro experiments showed that a novel population of multinucleated α-smooth muscle actin+CD90– myofibroblast-like cells, which surrounded fibrotic tissue, was the main source of OPN during progression of fibrosis. Since senescence-associated β-galactosidase activity was detected in those cells both in vitro and in vivo, these cells probably were terminally differentiated senescent myofibroblasts.
OPN has been implicated in fibrosis in several organs. Our results suggest potential roles of OPN and its main source, the senescent myofibroblasts, in glomerular fibrosis.
PMCID: PMC2980521  PMID: 20714131
Fibrosis; Anti-glomerular basement membrane disease; Fibroblast; Extracellular matrix; Inflammation

Results 1-3 (3)