Inhibition of Osteopontin Affects Glomerular Sclerosis and Crescent Formation in Animal Model of Anti-Glomerular Basement Membrane Disease.
John Hicks, Jean Wu, James Barrish, Shen-Hua Zhu, Ralph Nichols, Ya-Huan Lou. Texas Children's Hospital and Baylor College of Medicine, Houston; University of Texas Health Science Center at Houston
Background: Osteopontin (OPN) is an integrin-binding extracellular membrane glycophosphoprotein with a role in inflammation, autoimmunity and fibrosis. Glomerular OPN is upregulated in progressive renal failure. Anti-OPN antibody treatment is associated with decreased proteinuria, improved renal function and decreased interstitial fibrosis.
Design: An established rat mode for autoimmune anti-glomerular basement membrane disease (Anti-GBM) induced by immunization with a T-cell epitope pCol(28-40) peptide derived from alpha3 Type IV collagen chain or by transfer of Col4alpha3-specific T-cells was employed to induce glomerular disease. With this model, there are two distinct stages of disease induction: 1) CD4 T-cell mediated glomerular inflammation followed by 2) severe fibrocellular/fibrous crescent formation. Female Wistar-Kyoto rats (4-6wks old) were used (n=10 treatment group, n=10 control group). Anti-GBM disease was induced with peptide in treatment group, while controls were immunized with vehicle solution only. At post-immunization days 26, 28, 33 and 38, anti-OPN was administered to treatment group. Animals were sacrificed at day 40. Kidneys were submitted for histopathologic (H&E, PAS, trichrome) and ultrastructural study.
Results: Anti-OPN markedly reduced fibrocellular/fibrous crescent formation. Animals with anti-OPN treatment resulted in crescent formation in 39.7% of glomeruli compared with 86.6% for the untreated controls (P<.05). Fibrotic crescents in anti-GBM group had only limited to small areas adjacent to Bowman's capsule affected versus global fibrotic crescent formation in controls. Global fibrotic crescents were not observed in anti-GBM group. Interstitial tissues were more severely affected in controls compared with anti-GBM group. Electron microscopy showed marked thickening, wrinkling of GBMs, foot process effacement, and mesangial matrix expansion with control group; while anti-GBM group had minimally thickened. wrinkled GBMs, less prominent mesangial matrix expansion, but foot process effacement. No electron dense deposits were noted with control or anti-GBM groups.
Conclusions: Anti-OPN treatment resulted in a marked reduction in fibrocellular/fibrotic crescent formation in an anti-GBM animal model with established crescentic disease, indicating that OPN may be a therapeutic target in anti-GBM disease and other crescentic glomerular diseases.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 275, Wednesday Morning