2001 Fiscal Year Final Research Report Summary
Application of anti-adhesion molecule therapy for glomerulonephritis -Effects of sulfated oligosaccharides as selectin-blocking agents-
| Project/Area Number |
11671036
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Okayama University |
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Principal Investigator |
SHIKATA Kenichi Okayama University, Hospital, Lecturer, 医学部・附属病院, 講師 (00243452)
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| Co-Investigator(Kenkyū-buntansha) |
HIDA Kazuyuki Okayama University, Hospital, Senior Resident, 医学部・附属病院, 医員
WADA Jun Okayama University, Graduate School of Medicine and Dentistry, Assistant, 大学院・医歯学総合研究科, 助手 (30294408)
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| Project Period (FY) |
1999 – 2000
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| Keywords | glomerulonephritis / macrophage / adhesion molecule / selectin / hyaluronic acid / colominic acid / iNOS / therapy |
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| Research Abstract |
Background. Selectins are adhesion molecules which mediate leukocyte infiltration into inflammatory tissues. P- and L-selectin bind to sulfated oligosaccharide chains on the ligand molecules. Synthesized sulfated oligosaccharides, including sulfated hyarulonic acid (SHA) and sulfated colominic acid (SCA), inhibit both P- and L-selectin-dependent adhesion pathways in vitro. We evaluated the preventive effects of SHA and SCA on rat mesangial proliferative glomerulonephritis and rat crescentic glomerulonephritis.
Methods. Female Wistar rats were injected with anti-Thy-1 antibody after unilateral nephrectomy for a mesangial proliferative glomerulonephritis model. Female WKY rats were injected with nephrotoxic serum for a crescentic glomerulonephritis model. Rats were administered with neutralizing or non-neutralizing monoclonal antibodies to rat P-selectin and L-selectin, SHA, hyarulonic acid, SCA and colominic acid. Localization of P-selectin and macrophages were examined by immunohistochemical methods. Gene expression of PDGF B chain in the glomeruli was quantified using real-time RT-PCR method.
Results. Increased expression of P-selectin and macrophage infiltration was prominent in the glomeruli in both two models. Proteinuria, crescent formation and glomerular infiltration of macrophages were significantly reduced by anti-P-selectin mAb, but not by anti-L-SL mAb. SHA and SCA reduced proteinuria, macrophage infiltration and crescent formation in dose dependent manner. Gene expression of PDGF B chain was significantly decreased in SHA and SCA treatment groups. In conclusion, SHA and SCA inhibited glomerular macrophage infiltration by blocking P-selectin-dependent adhesion pathway, and prevented disease progression in rat mesangial proliferative glomerulonephritris and rat crescentic glomerulonephritis. We conclude that sulfated oligosaccharides may be beneficial for the treatment of glomerulonephritis.
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