title: Genetic background-dependent thrombotic microangiopathy is related to vascular endothelial growth factor receptor 2 signaling during anti-glomerular basement membrane glomerulonephritis in mice.
abstract: Because genetic background plays a pivotal role in humans and in various experimental models, we carefully monitored its impact on glomerular pathological characteristics during experimental anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN), using two leading mouse strains, 129S2/SvPas (129Sv) and C57bl/6J (B6J). These mice exhibited different severities of renal failure, hypertension, and glomerular lesions, according to their genetic background. In addition to the classic glomerular proliferative lesions, glomerular thrombotic microangiopathy (TMA) was found as a common genetic background-dependent histopathological hallmark of anti-GBM-GN, combined with hemolytic anemia and thrombocytopenia. Glomerular expression profiling, using microarrays and Western blot analysis in B6J TMA-resistant and 129Sv TMA-prone mice, demonstrated major differences in vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) 2 pathways, despite similar Vegfa expression levels. Further analysis revealed a lower basal glomerular endothelial Vegfr2 expression level in 129Sv TMA-prone mice compared with B6J TMA-resistant mice. This difference was even more pronounced during anti-GBM-GN, explaining why an exogenous VEGFA supply failed to rescue any 129Sv TMA lesions. Conversely, the systemic blocking of Vegfr2 amplified TMA lesions only in B6J mice. Herein, we specified the role that genetic background plays in determining, in particular, the level of Vegfr2 expression. We also demonstrated that glomerular Vegfr2-dependent TMA lesions are an underevaluated common hallmark of anti-GBM-GN in mice.
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France; Emergency Nephrological and Renal Transplantation, the APHP, Hôpital Tenon, Paris, France. Electronic address: laurent.mesnard@tnn.aphp.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Cathelin
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Rafat
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Yosu
authors.initials: Y
authors.lastname: Luque
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Sohier
authors.affiliation: Anatomy and Pathology Service, the APHP, Hôpital Européen Georges-Pompidou, and Université Paris V, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Nochy
authors.affiliation: Biological Immunology and Hematology Service, the APHP, Hôpital Saint-Antoine, and Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Garcon
authors.affiliation: Anatomic Pathology Service, the APHP, Hôpital Tenon, and Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Callard
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Jouanneau
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Verpont
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Paris Cardiovascular Research Centre (PARCC), INSERM, Paris, France.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France; Emergency Nephrological and Renal Transplantation, the APHP, Hôpital Tenon, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hertig
authors.affiliation: INSERM Unité UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Hôpital Tenon, Paris, France; UMR-S 1155, Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, the Sorbonne Universités, UPMC University Paris, Paris, France; Emergency Nephrological and Renal Transplantation, the APHP, Hôpital Tenon, Paris, France. Electronic address: eric.rondeau@tnn.aphp.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Rondeau
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D057049:Thrombotic Microangiopathies / Q000235:genetics*; D046888:Tissue Array Analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2