| Project/Area Number |
09671176
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Kidney internal medicine
|
|---|
| Research Institution | JUNTENDO UNIVERSITY SCHOOL OF MEDICINE |
|---|
Principal Investigator |
TOMINO Yasuhiko DIVISION OF NEPHROLOGY,DEPARTMENT OF MEDICINE,JUNTENDO UNIVERSITY SCHOOL OF MEDICINE,PROFESSOR, 医学部, 教授 (60130077)
|
|---|
| Project Period (FY) |
1997 – 1998
|
| Project Status |
Completed (Fiscal Year 1998)
|
| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥1,300,000 (Direct Cost: ¥1,300,000)
|
|---|
| Keywords | Fc receptor / Fc receptor gamma chain / immunecomplex / IgA nephropathy / anti-GBM glomerulonephritis / renin-angiotensin system / Fc receptor gamma chain knockout mice / clearance / Fcレセプターr鎖 / レニン・アンギオテンシン系 / Fcレセプターr鎖ノックアウトマウス / メサンギウム細胞 / IgA免疫複合体 / FcαR / FcRγ鎖 / 分子的会合 / FcγRIIb / ノックアウトマウス |
|---|
| Research Abstract |
We have been focusing on pathogenesis of IgA nephropathy, especially the pathological meaning of IgA/IgA-IC, from the stand point of FcR.In this term, we analyzed the pathophysiological role of FcR in vivo. 1)To assess the physiological roles of FcR and approach the mechanisms of IC nephritogenic effects on glomeruli, we examined the kidneys of FcR gamma-chain knockout mice (gamma(-/-) mice) which congenitally lack functional FcR.Histological examination of gamma(-/-) mice showed that polyclonal immunoglobulins were gradually and massively accumulated in the paramesangial areas without glomerulonephritis and renal dysfunction. For further investigation of relevant FcR- bearing cell-types, bone marrow (wild type littermates) transplantation was performed in 54 weeks-age gamma(-/-) mice (gamma(-/-)IWT mice). Neither significant infiltration of leukocytes nor decrement of immune-deposits in the mesangium was found in gamma(-/-)/WT mice. Thereafter we next injected rabbit anti-mouse IgG Ab
… More
into gamma(-/-) and gamma(-/-.)/WT mice. Transient renal injuries were observed in gamma(-/-)/WT mice. The rabbit IgG-IC completely disappeared in gamma(-I-)/WT mice at 2 week after the injection, while the IC remained in gamma(-I-) mice. These data clearly demonstrated that FcR contribute to systemic and local clearance of Ab/IC in the physiological state. 2) Next we reevaluated anti-GBM antibody-induced GN (anti- GBM GN), in mice of two strains which are deficient in FcR gamma chain (gamma(-I-)) or FcgammaRIIB (RII(-/-)). In gamma(-/-) mice, renal injuries were dramatically attenuated, while RH(-/-) mice suffered accelerated glomerular injuries in spite of a normal PMN influx. Our results demonstrated that FcRs play a pivotal role in acute phase of anti-GBM GN.We further clarified the existence of FcR -independent but antibody-dependent pathway which lead to chronic renal damage. We hypothesized this pathway was related to renin-angiotensin system (RAS). By using chimeric mice of gamma(-/-) and angiotensin II receptor knockout mice antagonist, we proved FcR and RAS were critical determinants in anti-GBM GN.Our present data would contribute to the understanding for pathogenesis of IgA nephropathy. Less
|
