Distinct contribution of Fc receptors and angiotensin II-dependent pathways in anti-GBM glomerulonephritis

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 Fe receptors (FcRs) play critical roles in the inflammatory cascade. Wt 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 gamma chain [gamma(-/-)] or Fc gamma RIIB [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 receptor antagonist in gamma(-/-) mice. Results. In gamma(-/-) 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 PR IN influx. In the absence of FcR-dependent effects in gamma(-/-) mice. the FcR-independent nt 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 oc smooth muscle actin in the mesangial cells and interstitium. Those injuries in gamma(-/-) mice were not attenuated by the decomplementation, t,ut completely abolished by using an angiotensin II type 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.