A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy
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A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy. / Tomas, Nicola M; Meyer-Schwesinger, Catherine; von Spiegel, Hanning; Kotb, Ahmed M; Zahner, Gunther; Hoxha, Elion; Helmchen, Udo; Endlich, Nicole; Koch-Nolte, Friedrich; Stahl, Rolf A K.
In: J AM SOC NEPHROL, Vol. 28, No. 11, 11.2017, p. 3262-3277.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy
AU - Tomas, Nicola M
AU - Meyer-Schwesinger, Catherine
AU - von Spiegel, Hanning
AU - Kotb, Ahmed M
AU - Zahner, Gunther
AU - Hoxha, Elion
AU - Helmchen, Udo
AU - Endlich, Nicole
AU - Koch-Nolte, Friedrich
AU - Stahl, Rolf A K
N1 - Copyright © 2017 by the American Society of Nephrology.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies
KW - Antigens, Surface
KW - Disease Models, Animal
KW - Glomerulonephritis, Membranous
KW - Humans
KW - Male
KW - Membrane Proteins
KW - Mice
KW - Mice, Inbred BALB C
KW - Rabbits
KW - Rats
KW - Rats, Sprague-Dawley
KW - Thrombospondins
KW - Journal Article
U2 - 10.1681/ASN.2017010030
DO - 10.1681/ASN.2017010030
M3 - SCORING: Journal article
C2 - 28814510
VL - 28
SP - 3262
EP - 3277
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 11
ER -
