Experimental models of membranoproliferative glomerulonephritis, including dense deposit disease.
Membranoproliferative glomerulonephritis (MPGN) is characterised by mesangial expansion and hypercellularity and capillary wall thickening with capillary wall and mesangial deposits of immunoglobulin and/or complement. Two main forms are described in humans: MPGN type I with subendothelial and mesangial electron-dense deposits on electron microscopy, and MPGN type II, or dense deposit disease, with electron dense transformation of the glomerular capillary wall. Spontaneous MPGN type I has been described in dogs and sheep in association with C3 deficiency. Induced models of MPGN type I have been described in mice with cryoglobulinaemia. Glomerulonephritis resembling MPGN type II has occurred spontaneously in pigs that have a genetic deficiency of the complement control protein factor H. The animals develop capillary wall deposits of C3 before birth. Mice have been genetically engineered with a deficiency of factor H and similarly develop glomerular capillary wall C3 with MPGN. This model has been used to study both pathogenesis and therapeutic interventions. In particular, MPGN associated with factor H deficiency is absolutely dependent on both the ability to activate C3 and on the ability of factor I to cleave C3b. There is an important role for C5 activation in the development of glomerular inflammation in this model. Factor H dysfunction is associated with an increased susceptibility to complement-activating nephrotoxic insults and in these scenarios C5 activation appears to play a major role in mediating glomerular injury.
Katherine A
KA
Vernon
Matthew C
MC
Pickering
Terence
T
Cook
D000818:Animals; D003176:Complement C3 / Q000172:deficiency / Q000502:physiology; D003182:Complement C5 / Q000502:physiology; D017242:Complement Factor H / Q000172:deficiency / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D015432:Glomerulonephritis, Membranoproliferative / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D013552:Swine
D003176:Complement C3; D003182:Complement C5; D017242:Complement Factor H