IgA1 Protease Treatment Reverses Mesangial Deposits and Hematuria in a Model of IgA Nephropathy.

Abstract

IgA nephropathy (IgAN), characterized by mesangial IgA1 deposits, is a leading cause of renal failure worldwide. IgAN pathogenesis involves circulating hypogalactosylated IgA1 complexed with soluble IgA Fc receptor I (sCD89) and/or anti-hypogalactosylated-IgA1 autoantibodies, but no specific treatment is available for IgAN. The absence of IgA1 and CD89 homologs in the mouse has precluded in vivo proof-of-concept studies of specific therapies targeting IgA1. However, the α1KI‑CD89Tg mouse model of IgAN, which expresses human IgA1 and human CD89, allows in vivo testing of recombinant IgA1 protease (IgA1‑P), a bacterial protein that selectively cleaves human IgA1. Mice injected with IgA1‑P (1-10 mg/kg) had Fc fragments of IgA1 in both serum and urine, associated with a decrease in IgA1-sCD89 complexes. Levels of mesangial IgA1 deposits and the binding partners of these deposits (sCD89, transferrin receptor, and transglutaminase 2) decreased markedly 1 week after treatment, as did the levels of C3 deposition, CD11b(+) infiltrating cells, and fibronectin. Antiprotease antibodies did not significantly alter IgA1‑P activity. Moreover, hematuria consistently decreased after treatment. In conclusion, IgA1‑P strongly diminishes human IgA1 mesangial deposits and reduces inflammation, fibrosis, and hematuria in a mouse IgAN model, and therefore may be a plausible treatment for patients with IgAN.

• Authors: Sebastian M Lechner, Lilia Abbad, Erwan Boedec, Christina Papista, Marie-Bénédicte Le Stang, Christelle Moal, Julien Maillard, Agnès Jamin, Julie Bex-Coudrat, Yong Wang, Aiqun Li, Paolo G V Martini, Renato C Monteiro, Laureline Berthelot
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 27 Issue 9 Pg. 2622-9 (09 2016) ISSN: 1533-3450 [Electronic] United States
• PMID: 26850635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by the American Society of Nephrology.

Chemical References

• Immunoglobulin A
• Serine Endopeptidases
• IgA-specific serine endopeptidase

Topics

• Animals
• Disease Models, Animal
• Glomerular Mesangium (metabolism)
• Glomerulonephritis, IGA (drug therapy)
• Hematuria (drug therapy)
• Immunoglobulin A (drug effects, metabolism)
• Mice
• Serine Endopeptidases (pharmacology, therapeutic use)