Advances of the experimental models of idiopathic membranous nephropathy (1)
Mouse models of idiopathic membranous nephropathy (IMN)
- Thrombospondin type‐1 domain‐containing 7A‐associated membranous nephropathy (MN) model.
Thrombospondin type-1 domain‐containing 7A (THSD7A) is one of the target podocyte autoantibodies in IMN. THSd7a is strongly expressed in murine podocyte. This has enabled the establishment of a model of THSD7A-related MN, which is closer to human IMN. Human anti-THSD7A antibody-containing serum was injected in mice and the human anti-THSD7A autoantibodies can specifically bind to mouse (m)THSD7A. The mice manifest significant albuminuria around day 3 and until day 70. Immunofluorescence staining analyses revealed complement c3 accumulations within the subepithelial granular pattern.
A heterologous model of THSD7A-associated MN was introduced. Rabbit anti-THSD7A antibodies by co-immunization with a combination of mTHSD7A and human (h)THSd7a cDNAs. Then, the mice were injected with anti‐THSD7A IgG purified from rabbit serum. The mice that received rabbit IgGs developed severe nephritic syndrome and the albumin-to-creatinine ratio increased gradually during the entire observation period of 14 days. The mice presented the same histopathological changes as the abovementioned THSd7a-associated model, with the only differences being the unknown IgG hypotype and undetected C3.
APA is a hydrolase present in the kidney of mice and is mainly located on the podocyte membrane and the brush border of proximal tubules. The model was established by injecting anti-APA monoclonal antibodies in mice. The dose-dependent proteinuria lasted for 16 days but lacked activation of the complement system.
According to the negative characteristic of the GBM, injecting rabbits with cationic bovine serum albumin (c-BSA, pI>9.5) daily intravenously induced proteinuria and nephrotic syndrome approximately 2 weeks later. Immunofluorescence showed IgG, C3 and other granule depositions in the GBM. Due to the c-BSA deposited in the GBM, which is full of negative charge and the corresponding antibody (principally IgG1), produced by its own form of immune complex in situ, activates the complement pathway.
The non-collagen 1 domain of human α3 of type IV collagen (α3NC1) is a normal constituent of the GBM. Its higher isoelectric point (pI>9), it may be conducive to the formation of GBM deposition, similar to the mechanism of c-BSA. Mice immunized with α3NC1 develop clinical and histopathological features of IMN. The extent and quality of autoimmunity against α3NC1 and T-cell responses are critical to the severity of nephropathy. C3, C5b-9 and C5 are involved in the pathogenesis of the model. Only the DBA/1 mice are associated with a high success rate for mouse modeling and other mice have a certain degree of resistance to α3NC1 and cannot be used for developing such models.