TY - JOUR
T1 - Distinct contribution of Fc receptors and angiotensin II-dependent pathways in anti-GBM glomerulonephritis
AU - Suzuki, Yusuke
AU - Shirato, Isao
AU - Okumura, Ko
AU - Ravetch, Jeffrey V.
AU - Takai, Toshiyuki
AU - Tomino, Yasuhiko
AU - Ra, Chisei
N1 - Funding Information:
This work was supported partially by grants in aids from CREST (Core Research for Evolutional Science and Technology), Ministry of Education and Ministry of Health and Welfare, Japan. The authors are grateful to Drs. S.A. Park and T. Saito for the generation of γ(-/-) mice in a collaboration; to Dr. K. Hayasaka for electron microscopic studies; and to Drs. S. Shirai and S. Hirose for their helpful discussions. We also thank Dr. A. Kurusu and T. Shibata for excellent technical assistance.
PY - 1998
Y1 - 1998
N2 - Background. The contribution of antibody and/or immune-complex to the pathogenesis of immunologically-mediated glomerulonephritis is not fully understood, although it has been recently clarified that Fc receptors (FcRs) play critical roles in the inflammatory cascade. We therefore re-evaluated the classical model of glomerulonephritis, anti-glomerular basement membrane antibody-induced glomerulonephritis (Anti-GBM GN), from the standpoint of FcRs and also investigated the residual FcR-independent mechanisms. Methods. We adopted an Anti-GBM GN mouse model that has two strains deficient in the FcR γ chain [γ(-/-)] or FcγRIIB [RII(-/-)], and analyzed functional (urinary protein, serum creatinine, BUN) and pathological changes of the glomeruli. For the analyses of FcR-independent mechanisms, several doses of nephrotoxic serum were applied, and then mice were treated either with cobra venom factor or an angiotensin II type 1 receptor antagonist in γ(-/-) mice. Results. In γ(-/-) mice, renal injuries were dramatically attenuated with an absence of polymorphonuclear cell (PMN) influx, while RII(-/-) mice suffered accelerated glomerular injuries in spite of a normal PMN influx. In the absence of FcR-dependent effects in γ(-/-) mice, the FcR-independent pathway lead to chronic renal damage characterized by mesangial proliferation and progressive expansion of mesangial area, with monocyte/macrophage accumulation and with the expression of α smooth muscle actin in the mesangial cells and interstitium. Those injuries in γ(-/-) mice were not attenuated by the decomplementation, but completely abolished by using an angiotensin II type 1 receptor antagonist. Conclusions. Our results clearly demonstrate that FcRs play a pivotal role in Anti-GBM GN, especially in its acute phase. We further clarified the existence of FcR and complement- independent but antibody-dependent pathway. Furthermore, we found that those pathological changes were strongly related to the renin-angiotensin system.
AB - Background. The contribution of antibody and/or immune-complex to the pathogenesis of immunologically-mediated glomerulonephritis is not fully understood, although it has been recently clarified that Fc receptors (FcRs) play critical roles in the inflammatory cascade. We therefore re-evaluated the classical model of glomerulonephritis, anti-glomerular basement membrane antibody-induced glomerulonephritis (Anti-GBM GN), from the standpoint of FcRs and also investigated the residual FcR-independent mechanisms. Methods. We adopted an Anti-GBM GN mouse model that has two strains deficient in the FcR γ chain [γ(-/-)] or FcγRIIB [RII(-/-)], and analyzed functional (urinary protein, serum creatinine, BUN) and pathological changes of the glomeruli. For the analyses of FcR-independent mechanisms, several doses of nephrotoxic serum were applied, and then mice were treated either with cobra venom factor or an angiotensin II type 1 receptor antagonist in γ(-/-) mice. Results. In γ(-/-) mice, renal injuries were dramatically attenuated with an absence of polymorphonuclear cell (PMN) influx, while RII(-/-) mice suffered accelerated glomerular injuries in spite of a normal PMN influx. In the absence of FcR-dependent effects in γ(-/-) mice, the FcR-independent pathway lead to chronic renal damage characterized by mesangial proliferation and progressive expansion of mesangial area, with monocyte/macrophage accumulation and with the expression of α smooth muscle actin in the mesangial cells and interstitium. Those injuries in γ(-/-) mice were not attenuated by the decomplementation, but completely abolished by using an angiotensin II type 1 receptor antagonist. Conclusions. Our results clearly demonstrate that FcRs play a pivotal role in Anti-GBM GN, especially in its acute phase. We further clarified the existence of FcR and complement- independent but antibody-dependent pathway. Furthermore, we found that those pathological changes were strongly related to the renin-angiotensin system.
KW - Angiotensin II
KW - Anti-GBM antibody-induced glomerulonephritis
KW - FcR γ chain
KW - FcγRIIB
KW - Immune complex
KW - Monocyte/macrophage
KW - Polymorphonuclear cell
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U2 - 10.1046/j.1523-1755.1998.00108.x
DO - 10.1046/j.1523-1755.1998.00108.x
M3 - Article
C2 - 9767532
AN - SCOPUS:0031702690
SN - 0085-2538
VL - 54
SP - 1166
EP - 1174
JO - Kidney International
JF - Kidney International
IS - 4
ER -