Differential contribution of C5aR and C5b-9 pathways to renal thrombic microangiopathy and macrovascular thrombosis in mice carrying an atypical hemolytic syndrome-related factor H mutation.

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulated complement activation. Clinically, aHUS is effectively treated by an anti-C5 monoclonal antibody (mAb) but whether the disease is mediated by the C5a receptor (C5aR) or C5b-9 pathway, or both, is unknown. Here we address this in a factor H mutant mouse (FHR/R) which developed complement-mediated TMA as well as macrovascular thrombosis caused by an aHUS-related factor H point mutation (mouse W1206R, corresponding to human W1183R). C5 deficiency and anti-C5 mAb treatment blocked all disease manifestations in FHR/R mice. C5aR1 gene deficiency prevented macrovascular thrombosis in various organs but did not improve survival or reduce renal TMA. Conversely, C6 or C9 deficiency significantly improved survival and markedly diminished renal TMA but did not prevent macrovascular thrombosis. Interestingly, as they aged both FHR/R C6-/- and FHR/R C9-/- mice developed glomerular disease reminiscent of C3 glomerulonephritis. Thus, C5aR and C5b-9 pathways drove different aspects of disease in FHR/R mice with the C5aR pathway being responsible for macrovascular thrombosis and chronic inflammatory injury while the C5b-9 pathway caused renal TMA. Our data provide new understanding of the pathogenesis of complement-mediated TMA and macrovascular thrombosis in FHR/R mice and suggest that C5 blockade is more effective for the treatment of aHUS than selectively targeting the C5aR or C5b-9 pathway alone.

• Authors: Yoshiyasu Ueda, Takashi Miwa, Daisuke Ito, Hangsoo Kim, Sayaka Sato, Damodar Gullipalli, Lin Zhou, Madhu Golla, Delu Song, Joshua L Dunaief, Matthew B Palmer, Wen-Chao Song
• Journal: Kidney international (Kidney Int) Vol. 96 Issue 1 Pg. 67-79 (07 2019) ISSN: 1523-1755 [Electronic] United States
• PMID: 30910380 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• C5ar1 protein, mouse
• Complement C6
• Complement Membrane Attack Complex
• Receptor, Anaphylatoxin C5a
• Complement Factor H

Topics

• Animals
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Atypical Hemolytic Uremic Syndrome (drug therapy, genetics, immunology, pathology)
• Complement Activation (drug effects, genetics, immunology)
• Complement C6 (genetics, immunology, metabolism)
• Complement Factor H (genetics, immunology)
• Complement Membrane Attack Complex (genetics, immunology, metabolism)
• Disease Models, Animal
• Female
• Humans
• Kidney Glomerulus (blood supply, pathology, ultrastructure)
• Male
• Mice
• Mice, Transgenic
• Microscopy, Electron
• Point Mutation
• Receptor, Anaphylatoxin C5a (antagonists & inhibitors, genetics, immunology, metabolism)