title: Mannan-binding lectin-associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4.
abstract: Mannan-binding lectin-associated serine protease 2 (MASP-2) has been described as the essential enzyme for the lectin pathway (LP) of complement activation. Since there is strong published evidence indicating that complement activation via the LP critically contributes to ischemia reperfusion (IR) injury, we assessed the effect of MASP-2 deficiency in an isogenic mouse model of renal transplantation. The experimental transplantation model used included nephrectomy of the remaining native kidney at d 5 post-transplantation. While wild-type (WT) kidneys grafted into WT recipients (n=7) developed acute renal failure (control group), WT grafts transplanted into MASP-2-deficient recipients (n=7) showed significantly better kidney function, less C3 deposition, and less IR injury. In the absence of donor or recipient complement C4 (n=7), the WT to WT phenotype was preserved, indicating that the MASP-2-mediated damage was independent of C4 activation. This C4-bypass MASP-2 activity was confirmed in mice deficient for both MASP-2 and C4 (n=7), where the protection from postoperative acute renal failure was no greater than in mice with MASP-2 deficiency alone. Our study highlights the role of LP activation in renal IR injury and indicates that injury occurs through MASP-2-dependent activation events independent of C4.
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Campus, London, UK; and asgelham@gmail.com.
authors.forename: Elham
authors.initials: E
authors.lastname: Asgari
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Campus, London, UK; and.
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Farrar
authors.affiliation: Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lynch
authors.affiliation: Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Youssif M
authors.initials: YM
authors.lastname: Ali
authors.affiliation: Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Silke
authors.initials: S
authors.lastname: Roscher
authors.affiliation: Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Cordula
authors.initials: C
authors.lastname: Stover
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Campus, London, UK; and.
authors.forename: Wuding
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Wilhelm J
authors.initials: WJ
authors.lastname: Schwaeble
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Campus, London, UK; and.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Sacks
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D015933:Complement C3d / Q000378:metabolism; D003181:Complement C4 / Q000502:physiology*; D005260:Female; D007124:Immunoenzyme Techniques; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D011183:Postoperative Complications; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000601:surgery
chemical_list: C016759:C4b protein, mouse; D003181:Complement C4; D015933:Complement C3d; C491340:MASP-2 protein, mouse; D050606:Mannose-Binding Protein-Associated Serine Proteases
keywords: inflammation; kidney transplantation