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A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy
- Source :
- Journal of the American Society of Nephrology : JASN. 28(11)
- Publication Year :
- 2017
-
Abstract
- Thrombospondin type 1 domain-containing 7A (THSD7A) is a target for autoimmunity in patients with membranous nephropathy (MN). Circulating autoantibodies from patients with THSD7A-associated MN have been demonstrated to cause MN in mice. However, THSD7A-associated MN is a rare disease, preventing the use of patient antibodies for larger experimental procedures. Therefore, we generated antibodies against the human and mouse orthologs of THSD7A in rabbits by coimmunization with the respective cDNAs. Injection of these anti-THSD7A antibodies into mice induced a severe nephrotic syndrome with proteinuria, weight gain, and hyperlipidemia. Immunofluorescence analyses revealed granular antigen-antibody complexes in a subepithelial location along the glomerular filtration barrier 14 days after antibody injection, and immunohistochemistry for rabbit IgG and THSD7A as well as ultrastructural analyses showed the typical characteristics of human MN. Mice injected with purified IgG from rabbit serum that was taken before immunization failed to develop any of these changes. Notably, MN developed in the absence of detectable complement activation, and disease was strain dependent. In vitro, anti-THSD7A antibodies caused cytoskeletal rearrangement and activation of focal adhesion signaling. Knockdown of the THSD7A ortholog, thsd7aa, in zebrafish larvae resulted in altered podocyte differentiation and impaired glomerular filtration barrier function, with development of pericardial edema, suggesting an important role of THSD7A in glomerular filtration barrier integrity. In summary, our study introduces a heterologous mouse model that allows further investigation of the molecular events that underlie MN.
- Subjects :
- 0301 basic medicine
Male
Heterologous
Immunofluorescence
Glomerulonephritis, Membranous
Antibodies
Podocyte
Rats, Sprague-Dawley
03 medical and health sciences
Mice
Membranous nephropathy
medicine
Animals
Humans
Thrombospondin
Mice, Inbred BALB C
medicine.diagnostic_test
Chemistry
Membrane Proteins
General Medicine
medicine.disease
Molecular biology
Complement system
Rats
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Basic Research
Nephrology
Antigens, Surface
Glomerular Filtration Barrier
Immunohistochemistry
Rabbits
Thrombospondins
Subjects
Details
- ISSN :
- 15333450
- Volume :
- 28
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Accession number :
- edsair.doi.dedup.....c286f38cf7c08c9971b51caee12b13cb