A murine model of site-specific renal microvascular endothelial injury and thrombotic microangiopathy.
Despite the importance of endothelial injury and healing for primary and secondary renal disease and the availability of genetically engineered mouse models, to date no generally applicable murine disease model with site-specific renal endothelial injury has been established. We induced specific microvascular renal injury via selective renal arterial perfusion of the lectin concanavalin A (Con A) followed by sheep anti-concanavalin A and harvested tissues after 4 h, 24 h, days 3 and 7. Compared to control kidneys, histological evaluation demonstrated endothelial cell injury with subsequent complement, and platelet activation and thrombosis by light and electron microscopy. Mouse kidneys showed histologic evidence of severe glomerular and peritubular microvascular thrombosis with acute tubular necrosis, proteinuria, increased BUN and presence of schistocytes. Initial cell death of intrinsic renal cells resulted in a decrease of the glomerular cell count by 50% after 4 h followed by a proliferative response of glomerular (day 3, P < 0.05), interstitial (day 3, P < 0.05) and tubular cells leading to increased total glomerular cell count by day 7. This study establishes the Con A anti-Con A model as specific endothelial injury model in the mouse kidney providing a novel tool for investigating endothelial injury and repair mechanisms as well as elucidating the role of platelets in genetically engineered mice.
Hohenstein
Bernd
B
Department of Nephrology and Hypertension, University Erlangen-Nuremberg, Loschgestrasse 8, 91054 Erlangen, Germany.
Braun
Andrea
A
Amann
Kerstin U
KU
Johnson
Richard J
RJ
Hugo
Christian P M
CP
D000818:Animals; D017209:Apoptosis; D003208:Concanavalin A / Q000633:toxicity; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007678:Kidney Glomerulus / Q000648:ultrastructure; D007683:Kidney Tubular Necrosis, Acute / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D008854:Microscopy, Electron; D008934:Mitogens / Q000633:toxicity; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology / Q000473:pathology*; D012079:Renal Circulation; D012720:Severity of Illness Index; D013927:Thrombosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D008934:Mitogens; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D003208:Concanavalin A